Method For Total Synthesis Of Ecteinascidins And Intermediate Compounds Thereof

ABSTRACT

An intermediate compound for total synthesis of ecteinascidins comprising, a compound represented by general formula 2 having thioether group at C4 site, and the substituent R 2  of N 12  site is trichloroethoxicarbonyl (Troc) to which various substituents can be introduced by mild condition, further having 10 members ring structure which can be converted to a ring of other numbered members.

CROSS-REFERENCE

This application is a divisional of U.S. patent application Ser. No.10/498,367, filed Jun. 10, 2004.

FIELD OF THE INVENTION

The present invention relates to an intermediate compounds useful forthe total synthesis of ecteinascidin 743 (hereinafter shortened to Et743) having high antineoplastic activity, the analogous structuralcompounds to Et 743 and the method for synthesis of Et 743.

BACKGROUND OF THE INVENTION

Ecteinascidins is a group of marine alkaloid having antineoplasticitywhich is isolated from the extracted products from marine tunicatehabitat of Caribbean sea by very small amount. Among the ecteinascidins,since Et 743 has a very strong antineoplastic activity, theinvestigation to put it into practical use as a carcinostatic agent islimited, and the phase II clinical tests are now carried out in tenseveral countries in Europe and America. It is known that Et 743 has aneffect to depress the proliferation of cancer cells by 10 to 100 timesmore potent than (IC50=0.1-1 nM) Toxol, Camptotesin, Adriamycin orMitomycin which are currently used carcinostatic agent.

From the back ground mentioned above, various investigations forsynthesis were carried out, however, the complete synthesis was onlyreported by Prof. E. J. Corey of Harvard University in U.S.A. (J. Am.Chem. Soc. 1996, 118, 9202-9203, reference document A).

In the process of synthesis of the total synthesis disclosed in DocumentA (refer to page 9202), the feature of process is existing in the pointthat Et 743 is synthesized from the analogous compound to the compoundrepresented by general formula 1 of the present invention viaintermediates 4 and 8. That is, according to said process, C₄ site ofring B (regarding indication of ring, and the sites of atoms composing6-members ring, refer to general formula 1) which composes 6-membersring is formed from the intermediate 4 at the first step. And, since tothe atom C₄ composing B ring of 6-membered ring H which lacks reactivityis bonded, it becomes necessary to oxidation reaction to C₄ site on Bring. This oxidation reaction is not effective and is carried out byharsh condition, therefore, the production by industrial scale isdifficult and also the yield is not good. Further, since atom N₁₂ siteof the synthesized intermediate is substituted by alkyl group whichlacks reactivity, in this case substituted by methyl group, it is notsuited to the synthesis for various compounds. Although the totalsynthesis was reported, the supplying source of Et 743 is stilldepending on the natural sample whose supplying amount is very sacacity,therefore, the establishment of the method for a large scale productionof Et 743 is desired by accomplishing an effective synthesizing process.

Since, Et 743 is known as a medicine having high antineoplasticity, andphthalascidin induced from the intermediate product at the synthesis ofEt 743 displays same activity to Et 743, the establishment of theeffective and mild method for synthesis of Et 743 and analogous compoundthereof is strongly desired.

Therefore, the subject of the present invention is basically toaccomplish the effective method for total synthesis of Et 743, further,to provide not only Et 743 but also analogous compounds.

To dissolve the subject, the present invention tried the rstrosyntheticanalysis promises easy synthesis. And it will be possible to form B ringby ring forming reaction at ortho position of phenol which composes Aring to inner molecular aldehyde in a generated compound by 4-8reaction. Further, the inventors of the present invention consideredthat the generated compound by 4-8 reaction will be possible tosynthesize based on the polycondensation reaction of general formula 4,and general formula 5 via a compound of general formula 3, the totalsynthesis of Et 743, which is the aimed compound, by way of thecompounds represented by general formulae 5, 4, 3, 2 and 1 and thespecific structure of general formulae 1 and 2. And confirmation of thesynthetic rout enable for providing the analogous compound of Et 743.

DISCLOSURE OF THE INVENTION

The first one of the present invention is an intermediate compound fortotal synthesis of ecteinascidins comprising, a compound represented bygeneral formula 1 having thioether group at C₄ site, and the substituentR₂ of N₁₂ site is trichloroethoxicarbonyl to which various substituentscan be introduced by mild condition, further having 10 members ringstructure which can be converted to a ring of other numbered members,

wherein, Y is O or NH, X₂, X₃ and X₄ are independently selected from thegroup consisting of H or alkyl group of carbon number 4 or less,alkoxyalkyl group, allyl group, or alkyl or arylsulfonyl group, R₁ andR₄ is H or alkyl group of carbon number 4 or less, R₂ is alkoxycarbonylgroup which can be substituted by halogen, lower alkyl sulfonyl or arylsulfonyl group and R₃ is nitrile or OH.

The second one of the present invention is a method for synthesis of thecompound of general formula 1 having the processes displayed by thereaction 5-1 which is transforming reaction of C₁₈ hydroxyl group toallyl ether and C₂₂ acetyl group to hydroxyl group, the reaction 5-2which is introducing reaction of cysteine derivatives into C₂₂ acetylgroup and the reaction 5-3 which is C₄ thioetherification reaction andtransforming reaction of C₅ hydroxyl group to acetyl group, wherein Y isO, X₂ is Ac, X₃ is H, R₁ is Me, R₂ is Troc, R₃ is CN, and X₄ and R₄ aresame as to general formula 1.

The third one of the present invention is an intermediate compound fortotal synthesis of ecteinascidins having pentacyclic backbone ofecteinascidins, a compound represented by general formula 2 having OHgroup at C₄ and the substituent R₂ of N₁₂ is trichloroethoxicarbonyl(Troc) to which various substituents can be introduced by mildcondition,

wherein, Y is oxygen or NH, X₁ is hydroxyl group or protecting group ofamino group, X₂, X₃ and X₄ are independently selected from the groupconsisting of H or alkyl group of carbon number 4 or less, alkoxyalkylgroup, allyl group, or alkyl or arylsulfonyl group, R₁ and R₄ are H oralkyl group of carbon number 4 or less, R₂ is alkoxycarbonyl group whichcan be substituted by halogen, lower alkyl sulfonyl or aryl sulfonylgroup, and R₃ is nitrile or OH,

Desirably, the third one of the present invention is the intermediatecompound for total synthesis of ecteinascidins represented by generalformula 2, wherein, Y is O, X₁ is selected from silyl groups consistingof acyl group of carbon number 4 or less, TBDPS, TIPS, TBS, TES and TMS,X₂ and X₃ are allyloxy group, or alkoxy group of carbon number 4 or lessor alkoxyalkoxy group, R₃ is CN and R₄ is alkyl group of carbon number 4or less.

The fourth one of the present invention is a method for synthesis of thecompound of general formula 2 consisting of the processes displayed bythe reaction 4-1 which transforms C₅ messily group to acetyl group, thereaction 4-2 which is the transforming reaction of N₁₂ t-butoxycarbonylgroup to trichloroethyl group, the reaction of 4-3 which is hydrationreaction of C₃₋₄ double bond, the reaction 4-4 which is the transformingreaction of C₄ hydroxyl group to TBS group and transforming reaction ofC₂₂ and C₅ acetyl group to hydroxyl group, the reaction 4-5 which istransforming reaction of C₅ hydroxyl group to benzyl group, reaction 4-6which is reduction reaction of C₂₁ amide and ring dosing reaction ofoxazolidine, the reaction 4-7 which is ring opening reaction ofoxazolidine and transforming reaction of C₂₂ hydroxyl group to acetylgroup, the reaction 4-8 which is oxidation reaction of C₂ hydroxyl groupto aldehyde and the reaction 4-9 which is transforming reaction of C₅,C₁₈ benzyloxy groups to hydroxyl group and ring forming reaction of Bring, wherein Y is O, X₂ is H, X₃ is H, R₃ is CN, X₁ is Ac, X₄, R₁ andR₄ are same to the general formula 2.

The fifth one of the present invention is an intermediate compound forthe compound of general formula 2 represented by general formula 3comprising the carbon locating at C₁₀ site at pentacyclic backbone ofecteinascidins of general formula 2 is bonded with H.

In general formula 3, R₁, R₂ and R₄, X₁-X₄ are same as to these ofgeneral formula 2.

Desirably, the fifth one of the present invention is the intermediatecompound for the compound represented by general formula 3, wherein Y isO, X₁ is selected from silyl groups consisting of acyl group of carbonnumber 4 or less, TBDPS, TIPS, TBS, TES and TMS, X₂ and X₃ are allyloxygroup, or alkoxy group of carbon number 4 or less or alkoxyalkoxy group,R₃ is CN and R₄ is alkyl group of carbon number 4 or less.

The sixth one of the present invention is the method for synthesis ofthe compound of general formula 3 consisting of the processes displayedby the reaction 3-1 which is the Ugi's 4 components condensationreaction, the reaction 3-2 which is the transforming reaction of C₂₂TBTPS group to acetyl group, the reaction 3-3 which is C ring formingreaction, the reaction 3-4 which is transforming reaction of C₅ hydroxylgroup to mesyl group, the reaction 3-5 which is reduction of C₁₁ amideand dehydration reaction of C₃₋₄ double bond and reaction 3-6 which isthe construction of D ring by Heck reaction, wherein Y is O, X₁ is Ac,X₂ is Ms and R₂ is Boc, X₃, X₄, R₁ and R₄ are same as to the generalformula 2.

The seventh one of the present invention is the amine compound whichprovide a segment to form a chemical structural site of A ring side ofthe intermediate compound of general formula 3 represented by generalformula 4 by Ugi reaction.

In general formula 4, R₄, X₂, Y and X₁ is same as to these of generalformula 2.

Desirably, the seventh one of the present invention is the aminecompound, wherein Y is O, X₁ is selected from the group of silyl groupsconsisting of acyl group of carbon number 4 or less, TBDPS, TIPS, TBS,TES and TMS.

The eighth one of the present invention is a method for synthesis of thecompound of general formula 4 consisting of the processes displayed bythe reaction 2-1 which is the transforming reaction from C₅ hydroxylgroup to methoxymethyl group, reaction 2-2 which is the introducingreaction of hydroxyl group to C₂₂, reaction 2-3 which is the Mannichreaction, reaction which is the transforming reaction of C₆ hydroxylgroup to trifluoromethanesulfonyl group (Tf), reaction 2-5 which is thereducing reaction of lactone, reaction 2-6 which is the transformingreaction of C₂₂ hydroxyl to TBDPS group, reaction 2-7 which is themethylation reaction of C₆ Tfo group and reaction 2-8 which is thetransforming reaction to amine, wherein Y=O, X₁ is TBOPS, X₂ is MOM andR₄ is Me.

The ninth one of the present invention is the carboxylic acid compoundwhich provides a segment forming a chemical structural site of E ringside of the intermediate compound of general formula 3 represented bygeneral formula 5 by Ugi reaction.

In general formula 5, R₁, R₂, X₃ and X₄ are same as to those of generalformula 1.

Desirably, the ninth one of the present invention is the carboxylic acidcompound wherein, X₃ and X₄ are independently selected from the groupconsisting of H or alkyl group of carbon number 4 or less, alkoxyalkylgroup, allyl group, allyl group, alkyl or arylsulfonyl group, R₂ isalkoxycarbonyl group, lower alkylsulfonyl or arylsulfonyl group whichcan be substituted by halogen.

The tenth one of the present invention, is the method for synthesis ofthe compound of general formula 5 consisting of the processes displayedby the reaction 1-1 which is the introducing reaction of formyl group toC₂₀, the reaction 1-2 which is the transforming reaction of C₂₀ formylgroup to dimethylacetal, the reaction 1-3 which is the iodinationreaction of C₁₉ and acidic hydrolysis reaction, the reaction 1-4 whichis the transforming reaction of C₁₋₈ hydroxyl group to benzyl group, thereaction 1-5 which is Honor-Emons reaction, reaction 1-6 which is theasymmetric reducing reaction by Duphos-Rh synthetic catalyst andreaction 1-7 which is the hydrolysis reaction of methylester, wherein R₂is Boc, X₃ is Bn, X₄ is Me, ring and R₁ is same as to it of generalformula 2.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will be illustrated more in detail according tothe following description.

-   A. As mentioned above, the first feature of the present invention is    the B ring forming reaction at ortho position of phenol which    composes A ring to aldehyde indicated by reaction 4-9 process in    synthesis process of the compound of the general formula 2. The    feature of this reaction is that the reaction is progressed by a    mild neutralized condition. Having OH group at the C₄ site which is    expressed as the structural feature of the compound represented by    general formula 2, the mild reaction condition is superior, since    the compound disclosed in above mentioned prior art has hydrogen at    this site, the reaction under harsh condition is required.    Furthermore, from this synthesis intermediate, the synthesis of    various analogous compounds is possible, and there is a possibility    to obtain a compound having antineoplastic activity such as    phtharasacidin being equal to Et 743.-   B. The second feature of the present invention is depending on that    utilizing the Ugi's 4 components condensation reaction of mentioned    3-1 reaction and Heck reaction of reaction 3-6 as the key process.    First of all, in the Ugi's 4 components condensation reaction of    3-1, no condensation reagents is required for the generation of    amide bond. The compound 3-1 make it possible to progress easily the    formation of C ring of reaction 3-3. The ring forming reaction of    reaction of 3-6 is not only the stereo chemistry of C₃ site    controlled perfectly, but also can proceed the reaction using    catalytic amount of Pd₂(dba)₃, which is an expensive reagent, by    catalytic amount.-   C. The third feature of the present invention is that the amine    represented by general formula 4 and the carboxylic acid represented    by general formula 5 can be provided by a large scale production.-   D. The fourth feature of the present invention is the ring forming    reaction of 10 members ring shown by reaction 5-3 process caused by    bonding of sulfur atom at C₄ site. The compound of the present    invention, to the C₄ site of which a hydroxyl group is introduced,    is possible to generate a cation of benzyl site easily under the    acidic condition, therefore, the ring formation of 10 members ring    by catching of sulfur atom to said cation is proceeded by high    yield. When compared with the case which uses the compound whose C₄    site is H reported by Prof. E. J. Corey, the method of the present    invention can use more mild condition. Therefore, the method of the    present invention has the advantage for easily accomplishing of    scale up, further has the possibility to introduce the ring of    various numbers of member and is useful for the synthesis of various    derivatives.

EXAMPLE

The present invention will be illustrated more in detail according tothe specified Examples, however, these Examples are aiming easilyunderstanding of the present invention and not intending to limit thescope of the claim of the present invention.

Example 1

The synthesis of compound 2-8, wherein Y contained in general formula 4is O, X₁ contained in general formula 4 is TBDPS, X₂ contained ingeneral formula 4 is MOM and R₄ contained in general formula 4 is Me.The reaction process and the whole chemical formula of the generatedcompounds in each reaction process are shown by following synthesisprocess A.

Synthesis Process A;

Detail of Synthetic Process A; (1) Synthesis of Compound 2-1

NaH (40 g, 1.0 mol) was dispersed in 700 ml of the mixed solution of THFand DMF (5:2), THF solution (300 ml) of 3,4-methylenedioxyphenol (138 g,11.0 mol) was dropped at 0° C. After stirred at room temperature for 30minutes, MOMCl (84.5 g, 1.05 mol) was dropped and stirred at roomtemperature for 1 hour. Hexane and water were added to the reactionsolution and the organic layer was separated. After the water layer wasextracted by hexane, the organic layer was concentrated by vacuum. Theresidue was dissolved in hexane, washed by brine, then dried by Na₂SO₄.After concentrated by vacuum, the residue was distilled by vacuum (103°C./0.35 mmHg), and the compound 2-1 (177 g, 0.97 mol, 97%) was obtainedas a colorless oil. The physical property of compound 2-1 is shown inTable 1.

TABLE 1 Compound 2-1 IR (neat film) 1244, 1215, 1176, 1153, 1099, 1069,1040, 1004, 940, 922, 842, 813 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.71 (d,J = 8.4 Hz, 1H) 6.63 (s, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.90 (s, 2H),5.08 (s, 2H), 3.46 (s, 3H); ¹³C NMR (100 MHz, CDCl₃), δ 152.5, 148.1,142.5, 108.4, 108.0, 101.2, 99.7, 95.4, 55.8.

Synthesis of Compound 2-2

After n-BuLi (3.02 mol n-hexane solution, 11.0 ml, 33.2 mmol) wasdropped in THF (100 ml) solution of compound 2-1 (5.44 g, 29.9 mmol) at0° C., the temperature was elevated to room temperature. The reactionsolution was cooled down to 0° C., B(OOMe)₃ (4.10 ml, 36.1 mmol) wasadded, then AcOH (3.4 ml, 59 mmol) and aqueous solution of 7% H₂O₂ (26ml, 60 mmol) were added. The reaction solution was stirred for 4.5 hoursat room temperature, saturated aqueous solution of (NH4)₂SO₄ (100 ml)and saturated aqueous solution of Na₂SO₃ (100 ml) were added, and anorganic layer was dried with MgSO₄ then concentrated by vacuum. Theresidue was purified by silica gel chromatography (70% EtOAc inn-haxane), and the compound 2-2 (5.42 g 27.3 mmol) was obtained as acolorless oil. The physical property of compound 2-2 is shown in Table2.

TABLE 2 Compound 2-2 IR (neat film) 3439, 1652, 1493, 1292, 1245, 1157,1044, 932, 791 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.55 (d, J = 8.4 Hz, 1H),6.45 (br, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.94 (s, 2H), 5.09 (s, 2H),3.50 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 144.3, 141.3, 134.4, 132.0,109.2, 101.6, 99.1, 97.3, 60.4, 56.3

Synthesis of Compound 2-3

As the method for synthesis of agent lactone (agent-1) which is added inthe reaction 2-3, document, for example, {“Synthesis of Optically ActiveArylglycines; Stereoselective Mannich Reaction of Phenols with a NewChiral template,” S. Tohma, A. Endo, T. Kan, T. Fukuyama, Synlett,1479-1499 (2001).} can be mentioned.

In CH₂Cl₂ (200 ml) solution of the compound 2-2 (19.8 g, 100 mmol) andagent-1 (20.3 g, 100 mmol), TFA (38 ml, 0.49 mol, 5 equiv) was droppedby 1.5 hours at −10° C. After the reaction solution was stirred for 40minutes at room temperature, Na₂CO₃ (40 g, 0.38 mol, 3.8 equivalent) andH₂O (200 ml) were added and extracted by CH₂Cl₂. The water layer wasextracted by CH₂Cl₂, then the organic layer was washed by brine, driedby Na₂SO₄ and concentrated by CH₂Cl₂. The residue was purified by silicagel chromatography (30% EtOAc in n-haxane), and the compound 2-3 (35.6 g89 mmol, 89%) was obtained a colorless oil. The physical property ofcompound 2-3 is shown in Table 3.

TABLE 3 Compound 2-3 [α]D²⁷ −75.2° (c = 1.65, CHCl₃); IR (neat film)3327, 1724, 1506, 1457, 1299, 1151, 1118, 1082, 1049, 1101, 934 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 9-7.37 (m, 5H), 6.51 (s, 1H) 5.93 (s, 1h), 5.91(d, J = 8.0 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 5.03 (s, 1H) 415 (s, 1H),3.51 (s, 3H), 2.03 (br, 1H), 1.37 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ169.0, 141.8, 141.4, 138.2, 134.8, 132.4, 128.4, 128.3, 128.3, 111.6,110.0, 101.9, 86.7, 61.0, 57.1, 56.4, 26.6, 22.0;

Synthesis of Compound 2-4

To the solution of the compound 2-3 (242 mg, 0.603 mmol) and pyridine(0.15 ml, 1.9 mmol), Tf₂O (0.13 ml, 0.77 mmol, 1.3 equivalent) wasdropped at 0° C. After the reacted product was stirred for 5 minutes,the aqueous solution of saturated NaHCO₃ was added and extracted byEtOAc. The organic layer was washed by the aqueous solution of 1N HCland the saturated aqueous solution of NaHCO₃, then dried by MgSO₄ andconcentrated by vacuum. The residue was purified by silica gelchromatography (in 50% EtOAc n-hexane), and the compound 2-4 (290 mg,0.544 mmol, 90%) was obtained as a colorless oil. The physicalproperties of the compound 2-4 are shown in Table 4.

TABLE 4 Compound 2-4 [α]D²⁶ −32.1° (c = 2.59, CHCl₃); IR (neat film)3333, 1733, 1496, 1462, 1427, 1299, 1216, 1138, 1056, 999, 979, 936, 832cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.40 (m, 5H), 6.71 (s, 1H) 6.06 (s,1H), 6.03 (s, 1H), 5.19 (d, J = 5.8 Hz, 1H), 5.14 (d, J = 5.8 Hz, 1H),5.09 (s, 1H) 4.23 (s, 1H), 3.49 (s, 3H), 2.01 (br, 1H), 1.40 (s, 6H);¹³C NMR (100 MHz, CDCl₃) δ 167.8, 144.9, 141.2, 140.2, 137.8, 128.3,128.2, 128.1, 123.1, 120.2, 116.7, 108.0, 103.1, 95.9, 86.7, 61.3, 56.9,56.3, 26.4, 21.8

Synthesis of Compound 2-5

To the MeOH (50 ml) solution of the compound 2-4 (4.70 g, 8.8 mmol),NaBH4 was added at 0° C. and stirred for 30 minutes. To the reactionsolution, EtOAc (300 ml) was added and washed by 1N HCl (100 ml). Theorganic layer was washed by saturated aqueous solution of NaHCO₃, andafter dried by MgSO₄, concentrated by vacuum. The residue was purifiedby silica gel chromatography (in 60% EtOAc n-hexane), and the compound2-5 (4.04 g, 7.5 mmol, 85%) was obtained as a colorless oil. Thephysical properties of the compound 2-5 are shown in Table 5.

TABLE 5 Compound 2-5 [α]D²⁷ −102° (c = 1.67, CHCl₃); IR (neat flim)3398, 1497, 1456, 1426, 1218, 1136, 1054, 937, 833 cm⁻¹; 1H NMR (400MHz, CDCl₃ ) δ 7.25-7.33 (m, 5H), 6.63 (s, 1H) 5.94 (s, 1H), 5.93 (s,1H), 5.11 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 6.8 Hz, 1H), 3.65 (br, 1H),3.52-3.64 (br, 2H), 3.50 (s, 3H), 3.39 (s, 1H), 2.71 (br, 1H), 1.11 (s,6H); ¹³C NMR (100 MHz, CDCl₃)δ 144.8, 141.6, 139.9, 139.2, 128.7, 128.1,127.5, 122.4, 120.9, 120.1, 116.9, 107.1, 102.9, 95.6, 72.7, 68.9, 64.9,56.9, 56.3, 27.9, 23.8;

Synthesis of Compound 2-6

To DMF solution of the compound 2-5 (1.00 g, 1.86 mmol) and imidazole(0.63 g, 9.3 mmol), TBDPSCl (1.22 ml, 4.7 mmol) was added and stirred atroom temperature. To the reacted product, Et₂O and water were added andthe organic layer was washed by brine, dried by Na₂SO₄ and concentratedby vacuum. The residue was purified by silica gel chromatography (in 10%EtOAc n-hexane), and the compound 2-6 (1.31 g, 1.69 mmol, 91%) wasobtained as a colorless oil. The physical properties of the compound 2-6are shown in Table 6.

TABLE 6 Compound 2-6 [α]D²⁷ −75.2°(c = 1.65, CHCl₃); IR (neat film)3445, 1469, 1428, 1363, 1263, 1109, 1062, 991, 944, 826 cm⁻¹; ¹H NMR(400 MHz, CDCl₃)δ 7.61 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H),7.23-7.42 (m, 11H), 6.62 (s, 1H), 5.83 (s, 2H), 5.10 (d, J = 6.8 Hz,1H), 5.08 (d, J = 6.8 Hz, 1H), 3.77 (dd, J = 6.0, 6.8 Hz, 1H), 3.67 (m,2H), 3.47 (s, 3H), 3.37 (s, 1H), 3.34 (br, 1H), 1.909 (s, 6H), 1.08 (s,9H); ¹³C NMR (100 MHz, CDCl₃)δ 144.7, 141.8, 139.8, 139.5, 135.6, 132.9,129.7, 128.5, 128.1, 127.7, 127.6, 127.4, 122.5, 121.0, 120.1, 116.9,107.7, 102.7, 95.8, 72.2, 68.6, 66.4, 56.8, 56.3, 27.4, 26.8, 24.2,19.2;

Synthesis of Compound 2-7

To the THF (105 ml) solution of the compound 2-6 (16.7 g, 21.5 mmol),MeZnCl (2.0M in THF solution, 37.5 ml, 75.1 mmol) was added at 0° C.After the temperature of the reaction solution was elevated to roomtemperature, PdCl₂ (dppf) (314 mg, 0.43 mmol) was added and refluxed byheating for 13.5 hours. EtOAc was added to the reaction solution, thenwashed by 1N HCl aqueous solution, saturated aqueous solution of NaHCO₃and brine. The organic layer was dried by Na₂SO₄ and concentrated byvacuum. The residue was purified by silica gel chromatography (in 10%EtOAc n-hexane), and the compound 2-7 (13.4 g, 20.9 mmol, 97%) wasobtained as a white solid. The physical properties of the compound 2-7are shown in Table 7.

TABLE 7 Compound 2-7 [α]D²⁶ −99.3° (c = 0.81, CHCl₃); IR (neat film)3457, 2931, 1494, 1457, 1427, 1362, 1216, 1139, 1110, 1056, 1006, 936,828 cm⁻¹; ¹H NMR (400 MHz, CDCl₃ δ 7.63 (d, J = 6.8 Hz, 2H), 7.56, (d, J= 6.8 Hz, 2H), 7.22-7.47 (m, 11H), 6.30 (s, 1H), 5.77 (s, 2H), 5.03 (d,J = 5.6 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 3.83 (dd, J = 10.8, 10.8,1H), 3.61-3.66 (m, 2H), 3.44 (s, 3H), 3.38 (s, 1H), 2.08 (s, 3H), 1.09(s, 9H), 1.06 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 150.8, 146.6, 140.0,139.7, 135.6, 135.6, 133.2, 133.1, 130.9, 130.4, 130.0, 129.7, 129.6,128.5, 128.4, 128.0, 127.7, 127.6, 127.2, 117.7, 109.6, 107.0, 100.8,95.6, 72.1, 68.5, 66.6, 57.7, 56.0, 27.3, 26.8, 24.0, 19.2, 8.8

Synthesis of Compound 2-8

To the CH₃CN (12 ml) solution of the compound 2-7 (640 mg, 1.0 mmol),Pb(OAc)₄ (0.56 g, 1.26 mmol) was added slowly at 0° C. To the reactionsolution, saturated aqueous solution of NaHCO₃ was added and extractedby EtOAc. The organic layer was washed by brine, dried by Na₂SO₄,concentrated by vacuum and crude product was obtained. The obtainedcrude product was dissolved in EtOH (10 ml), then hydrochloric acid saltof hydroxyl amine (347 mg, 5.6 mmol) and sodium acetate (410 mg, 5.0mmol) were added at room temperature and stirred for 1.5 hours. EtOAcwas added to the reaction solution, then filtrated by celite andconcentrated by vacuum. The residue was dissolved with EtOAc and washedby 1N HCl aqueous solution, saturated aqueous solution of NaHCO₃ andbrine. After the organic layer was dried by Na₂SO₄, concentrated byvacuum. The residue was purified by silica gel chromatography (EtOAc),and the compound 2-8 (436 mg, 0.88 mmol, 89%) was obtained. The physicalproperties of the compound 2-8 are shown in Table 8.

TABLE 8 Compound 2-8 [α]D²³ −1.99° (c = 1.30, CHCl₃); IR (neat film)1440, 1115, 1062, 991, 938, 826 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.61-7.65 (m, 4H), 7.35-7.45 (m, 6H), 6.57 (s, 1H), 5.81 (s, 2H), 5.09(s, 2H), 4.16 (dd, J = 6.8, 4.8 Hz, 1H), 3.87 (dd, J = 10.0, 4.8 Hz,1H), 3.76 (dd, J = 10.0, 6.8 Hz, 1H), 3.48 (s, 3H), 2.14 (s, 3H), 1.08(s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 150.8, 146.1, 139.1, 135.5, 135.5,133.4, 133.3, 129.5, 129.5, 127.5, 120.7, 109.1, 105.8, 100.7, 95.7,68.1, 55.9, 53.4, 26.7, 19.1, 8.8

Example 2

Synthesis of the compound 1-7 contained in general formula 5 The processfor synthetic reaction and the chemical structure of the productsobtained at each process are totally shown in following synthesisprocess B.

Synthesis Process B;

Detail of Synthesis of the Compound 1-7

Regarding the synthesis of bromide (starting material-1), for example,document of {“Synthetic Study on Ectenascidin 743 starting fromD-glucose” A. Entoh, T. Kan, and T. Fukuyama, Synlett, 1103-1105 (1999)}can be mentioned.

Synthesis of Compound 1-1

To the THF solution (900 ml) of the starting material-1 (114 g, 437mmol), n-BuLi (2.46M in n-hexane solution, 270 ml, 664 mmol) was addedat −78° C., then DMF (170 ml, 2.20 mol) was added. The temperature ofthe reaction solution was elevated to room temperature, and water wasadded to the reaction solution, then concentrated by vacuum. Et₂O wasadded to the residue, and washed by saturated aqueous solution of NaHCO₃and brine. After dried by MgSO₄, concentrated by vacuum. The residue waspurified by silica gel chromatography (30% Et₂O in n-hexane), and thecompound 1-1 (73.0 g, 347 mmol, 79%) was obtained as a colorless oil.The physical properties of the compound 1-1 are shown in Table 9.

TABLE 9 Compound 1-1 IR (neat film) 1699, 1585, 1488, 1451, 1382, 1299,1235, 1155, 1133, 1099, 1051, 1003, 928, 863 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 9.83 (s, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 5.25 (s, 2H), 3.90(s, 3H), 3.51 (s, 3H), 2.31 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 191.2,153.5, 150.5, 132.8, 132.1, 126.9, 114.2, 95.0, 60.3, 56.3, 16.0

Synthesis of Compound 1-2

To the MeOH solution (5.0 ml) of the compound 1-1 (331 mg, 1.57 mmol)and CH(OMe)₃ (1.0 ml, 9.14 mol), CSA (20.2 mg, 0.09 mmol) was added andrefluxed by heating fox 1 hour. K₂CO₃ (103 mg, 0.75 mmol) was added tothe reaction solution and concentrated by vacuum. The residue wasdissolved in Et₂O and filtrated by a column of basic alumina. Afterconcentrated by vacuum, the compound 1-2 (381 mg, 1.49 mmol, 94%) wasobtained as a colorless oil. The obtained compound 1-2 was used to thenext reaction without refining. The physical properties of the compound1-2 are shown in Table 10.

TABLE 10 Compound 1-2 1H NMR (400 MHz, CDCl₃) δ 7.05 (s, 1H), 6.93 (s,1H), 5.27 (s, 1H), 5.25 (s, 2H), 3.89 (s, 3H), 3.59 (s, 3H), 3.34 (s,3H), 2.32 (s, 3H)

Synthesis of Compound 1-3

To the Et₂O solution (4.0 ml) of the compound 1-2 (381 mg, 1.49 mmol),n-BuLi (2.46M in n-hexane solution, 0.95 ml, 2.34 mmol) was added at 0°C., then the temperature was elevated to room temperature. After reducedthe temperature of the reaction solution to 0° C., Et₂O (3.0 ml)solution of I₂ (648 mg, 2.55 ml) was added. After water and saturatedaqueous solution of NaHCO₃ were added, extracted by EtOAc. The organiclayer was washed by brine, dried by MgSO₄ and concentrated by vacuum.The residue was dissolved by THF (5.0 ml) and 12N HCl (2.0 ml) aqueoussolution was added at room temperature. After stirred for 15 minutes,neutralized by saturated aqueous solution of NaHCO₃ and extracted byEtOAc. The organic layer was washed by saturated aqueous solution ofbrine, dried by MgSO₄ and concentrated. The residue was dissolved byCH₂Cl₂ and filtrated by silica gel and concentrated by vacuum. Theobtained solid was washed by n-hexane and the compound 1-3 (314 mg, 1.07mmol, 72%), and the compound 1-3 was obtained as a colorless solid. Thephysical properties of the compound 1-3 are shown in Table 11.

TABLE 11 Compound 1-3 IR (neat film) 3389, 1670, 1583, 1464, 1412, 1299,1247, 1127, 997 cm⁻¹; ¹H NMR 400 MHz, CDCl₃) δ 10.0 (s, 1H), 7.37 (s,1H), 6.43 (bs, 1H), 3.89 (s, 3H), 2.32 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)δ 194.9, 149.9, 149.2, 131.3, 130.9, 125.3, 125.3, 60.8, 15.8;

The Synthesis of Compound 1-4

To the CH₃CN (3.0 ml) solution of the compound 1-3 (325 mg, 1.11 mmol)and K₂CO₃ (465 mg, 3.37 mmol) BuBr (140 μl, 1.18 mmol) were added atroom temperature and refluxed by heating for 40%. After CH₂Cl₂ wereadded to the reaction solution, filtrated by Celite, then concentratedby vacuum. The residue was purified by silica gel chromatography (50%CH₂Cl₂ in n-hexane), and the compound 1-4 (415 mg, 1.09 mmol, 98%) wasobtained as a colorless oil. The physical properties of the compound 1-4are shown in Table 12.

TABLE 12 Compound 1-4 IR (neat film) 1684, 1576, 1464, 1303, 1153, 1068,1005 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 10.0 (s, 1H), 7.60 (d, 8.0 Hz, 2H),7.59 (s, 1H), 7.30-7.45 (m, 3H), 5.01 (s, 2H), 3.93 (s, 3H), 2.30 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.3, 157.1, 151.3, 136.3, 133.3,131.3, 128.7, 128.5, 128.4, 128.2, 98.2, 74.9, 60.6, 15.7;

The Synthesis of Compound 1-5

To the CH₂Cl₂ solution (100 ml) of the compound 1-4 (8.30 g, 21.7 mmol)and methyl-2-butoxycarbonylamino-dimethylsulfonoacetate (7.76 g, 26.1mmol), TMG (4.10 ml, 32.7 mmol) was added at room temperature andstirred for 24 hours at room temperature. The reaction solution waswashed by 10% citric acid and saturated aqueous solution of NaHCO₃, thenthe organic layer was dried by MgSO₄ and concentrated by vacuum. Theresidue was purified by silica gel chromatography, and the compound 1-5(11.2 g, 20.2 mmol, 1.93%) was obtained as a yellow crystal. The furtherrefining was carried out by re-crystallization (EtOAc/n-hexane). Thephysical properties of the compound 1-5 are shown in Table 13.

TABLE 13 Compound 1-5 IR (neat film) 3336, 1717, 11457, 1367, 1249,1160, 1065, 1003 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 6.8 Hz,2H), 7.36-7.60 (m, 3H), 7.24 (s, 1H), 7.20 (s, 1H), 5.00 (s, 2H), 3.88(s, 3H), 3.86 (s, 3H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.6,152.4, 151.6, 136.8, 134.2, 132.5, 131.7, 128.7, 128.4, 128.2, 126.8,125.4, 96.9, 80.9, 74.6, 60.5, 52.7, 28.0, 15.8

The Synthesis of Compound 1-6

The EtOAC solution (30 ml) of frozen and degassed compound 1-5 (5.04 g,9.10 mmol) and Rh{(COD)-(S,S)-Et-DuPHOS} ⁺TfO— (99.0 mg, 0.14 mmol, 1.5mol %) was poured into a high pressure reactor and stirred for 22 hoursunder hydrogen atmosphere of 500 atm at 50° C. The reaction solution wasconcentrated by vacuum and the residue was purified by silica gelchromatography (50% EtOAc in n-hexane), and the compound 1-6 (5.01 g,902 mmol, 99%) was obtained as a light yellow crystal.

Wherein, (S,S)-Et-DuPhos-catalyst Rh{{(COD)-(S,S)-Et-DuPHOS}⁺TfO—} isshown as follows.

The physical properties of the compound 1-6 are shown in Table 14.

TABLE 14 Compound 1-6 [α]D²⁷ +7.4° (c = 1.09, CHCl₃); R (neat film)3374, 1764, 1711, 1510, 12457, 1363, 1162, 1068, 1003 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.60 (d, J = 8.8 Hz, 2H), 7.32-7.45 (m, 3H), 6.85 (s, 1H),5.06 (d, J = 8.8 Hz, 1H), 4.99 (s, 1H), 4.62 (ddd, J = 9.2, 8.8, 5.6 Hz,1H), 3.82 (s, 3H), 3.72 (s, 3H), 3.28 (dd, J = 14.4, 5.6 Hz, 1H), 3.09(dd, J = 14.4, 9.2 Hz, 1H), 2.23 (s, 3H), 1.43 (s, 9H); ¹³C NMR (100MHz, CDCl₃) δ 172.4, 154.9, 151.7, 150.4, 136.9, 135.4, 132.3, 128.6,128.4, 128.1, 127.8, 97.0, 79.8, 74.5, 60.4, 53.8, 52.3, 42.7, 28.2,15.6;

The Synthesis of Compound 1-7

LiOH (750 mg, 17.9 mmol, 2.0 equivalent) was added to the mixed solutionof compound 1-6 (5.01 g, 9.02 mmol) in MeOH (40 ml), H₂O (10 ml) and THF(10 ml) at 0° C. Benzene was added to the reaction solution andconcentrated by vacuum. 10% of aqueous solution of citric acid was addedto the residue and extracted by EtOAc. Organic layer was washed by brineand dried by MgSO₄ and concentrated by vacuum. Thus the compound 1-7(4.90 g, 9.05 mmol, 100%) was obtained as a white solid. The physicalproperty of the compound 1-7 is shown in Table 15.

TABLE 15 Compound 1-7 [α]D²⁷ −14.1° (c = 5.00, CHCl₃); IR (neat film)3309, 2560, 1716, 1497, 1471, 1404, 1368, 1307, 1243, 1163, 1063, 1008,907, 845, 804 cm⁻¹; 1H NMR (400 MHz, CDCl₃) δ 7.61 (br, 2H), 7.36-7.44(br, 3H), 6.90 (s, 1H), 5.00 (br, 2H), 4.63 (br, 1H), 3.83 (s, 3H), 3.43(br, 1H), 2.94-3.20 (br, 1H), 2.25 (s, 3H), 1.10-1.40 (br, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 176.2, 175.4, 156.7, 155.2, 151.4, 150.4, 150.3,136.9, 135.8, 135.3, 132.3, 132.2, 128.7, 128.6, 128.4, 128.4, 128.1,127.9, 97.1, 96.7, 81.1, 80.1, 77.2, 74.5, 60.4, 60.3, 54.1, 53.8, 53.7,44.6, 42.3, 42.2, 42.2, 28.2, 27.9, 15.6.

Example 3

The processes for synthesis of the compound 3-6 contained in generalformula 3 and whole products in each process are shown in followingsynthetic process C.

Synthetic Process C;

Detail of Synthesis of C; Synthesis of Compound 3-1

To the MeOH solution (200 ml) of compound 2-8 (9.63 g, 19.5 mmol),compound 1-7 (10.57 g, 19.5 mmol) and p-methoxyphenylisocyanide (3.90 g,29.3 mmol, 1.5 equivalent), acetaldehyde (22 ml, 0.39 mol, 20equivalent) was added at room temperature and refluxed for 1 hour. Afterconcentrated by vacuum, residue was purified by silica gelchromatography (40% EtOAc, n-hexane) and compound 3-1 (21.02 g, 17.6mmol, 90%) was obtained as a yellow solid. The physical properties of3-1 are shown in Table 16.

TABLE 16 Compound 3-1 IR (neat film) 3315, 1699, 1687, 1511, 1463, 1428,1367, 1245, 1159, 1112, 1062, 826 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.60-9.20 (m, 1H), 7.25-7.75 (m, 17H), 6.50-7.20 (m, 4H), 4.80-5.85 (m,9H), 3.90-4.80 (m, 3H), 3.60-3.85 (m, 6H), 3.40-3.50 (m, 3H), 2.90-3.50(m, 2H), 1.85-2.25 (m, 6H), 0.75-1.50 (m, 21H); ¹³C NMR (100 MHz, CDCl₃)δ 173.4, 172.0, 171.3, 170.1, 168.7, 167.9, 156.2, 156.1, 155.9, 155.6,155.3, 154.3, 151.5, 151.4, 151.3, 151.0, 150.9, 150.8, 150.5, 150.1,150.0, 146.9, 146.5, 139.8, 139.7, 136.8, 136.7, 136.6, 136.5, 135.6,135.5, 135.4, 135.3, 135.2, 132.6, 132.5, 132.4, 132.2, 132.1, 132.0,131.6, 131.1, 131.0, 129.9, 129.7, 129.6, 129.3, 128.5, 128.4, 128.3,128.2, 128.0, 127.9, 127.7, 127.5, 127.4, 127.3, 123.0, 121.7, 121.5,120.5, 113.7, 113.5, 113.4, 113.3, 113.1, 110.9, 106.2, 106.0, 100.9,100.6, 97.5, 96.7, 96.6, 96.2, 95.8, 95.5, 95.3, 80.6, 80.5, 80.3, 79.3,79.0, 74.4, 74.3, 71.5, 70.4, 62.6, 62.5, 60.2, 60.1, 59.7, 57.2, 56.2,56.1, 55.9, 55.1, 54.5, 54.4, 51.5, 51.3, 42.9, 41.8, 41.1, 41.1, 28.1,28.0, 27.9, 27.8, 27.1, 27.0, 26.9, 26.4, 19.1, 19.0, 18.9, 17.8, 17.1,15.4, 15.3, 15.2, 15.1, 14.9, 14.8, 8.8 8.7, 8.5;

Synthesis of Compound 3-2

TBAF (1M THF solution, 20 ml, 20.0 mmol) was added to THF solution (200ml) of compound 3-1 (21.02 g, 17.6 mmol) was added at room temperatureand stirred for 30 minutes. The mixed solvent of EtOH and n-hexane (3:7)was added and concentrated by vacuum. The residue was purified by silicagel chromatography (EtOAc) and yellow solid (14.90 g, 15.6 mmol, 89%)was obtained. DMPA (97 mg, 0.79 mmol) was added to the mixed solution ofacetic anhydride (30 ml) of alcohol (14.90 g, 15.6 mmol) and pyridine(60 ml) and stirred for 30 minutes at 50° C. After concentrated byvacuum, residue was purified by silica gel chromatography (60%, EtOAcn-hexane) and the compound 3-2 (14.54 g, 14.6 mmol, 93%) was obtained asyellow solid. The physical properties of compound 3-2 are shown in Table17.

TABLE 17 Compound 3-2 IR (neat film) 3318, 1743, 1700, 1511, 1436, 1368,1304, 1245, 1170, 1112, 1060, 830 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.90-9.30 (m, 1H), 7.55 (d, J = 6.8 Hz, 2H), 7.20-7.50 (m, 5H),6.30-7.20 (m, 2H), 6.80 (d, J = 6.8 Hz, 2H), 5.84-5.88 (br, 2H),5.60-5.80 (m, 2H), 5.20-5.45 (m, 2H), 5.00-5.20 (m, 2H), 4.93-4.97 (m,2H), 4.70-4.90 (m, 1H), 4.40-4.70 (m, 1H), 3.65-3.80 (m, 6H), 3.35-3.50(m, 3H), 2.90-3.35 M, 1H), 1.80-2.25 (m, 9H), 1.10-1.55 (m, 12H); ¹³CNMR (100 MHz, CDCl₃) δ 173.6, 173.2, 172.7, 172.0, 170.1, 170.0, 169.7,169.5, 169.5, 169.4, 168.2, 156.4, 156.1, 155.8, 155.2, 154.3, 151.5,151.3, 151.2, 151.2, 151.1, 150.6, 150.3, 147.1, 146.8, 146.6, 140.0,139.8, 139.3, 136.8, 136.7, 136.7, 136.5, 135.0, 134.9, 134.6, 132.5,132.0, 131.1, 131.0, 128.8, 128.5, 128.4, 128.4, 128.3, 128.2, 128.1,128.0, 127.9, 121.8, 121.8, 121.8, 121.6, 121.4, 121.2, 120.6, 113.9,113.9, 113.8, 113.5, 113.1, 112.6, 112.1, 111.7, 111.3, 105.9, 105.7,105.3, 101.1, 101.0, 100.7, 96.8, 96.5, 95.4, 95.1, 79.6, 79.1, 74.4,70.6, 62.0, 60.3, 60.2, 57.3, 56.5, 56.2, 56.0, 55.8, 55.2, 50.6, 50.1,43.5, 28.1, 28.0, 27.9, 27.8, 20.9, 20.7, 17.6, 15.3, 14.8, 8.8;

Synthesis of Compound 3-3

To the CH₂Cl₂ (290 ml) solution of compound 3-2 (14.5 g, 14.5 mmol) andanisole (79 ml, 0.73 mol), TFA (58 ml, 0.75 mol) was added at 0° C.,then stirred at room temperature for 9 hours. 7% Na₂SO₄ aqueous solutionwas added to the reaction solution and extracted by EtOAc. The organiclayer was washed by saturated aqueous solution of NaHCO₃ and by brine,dried by MgSO₄ and concentrated to 300 ml, then heat refluxed for 1hour. The solvent was evaporated off by vacuum, and the residue waspurified by column chromatography (in 70% EtOAc m-hexane). Thus thecompound 3-3 (19.7 g, 27.0 mmol, 87%) was obtained as a brownish powder.The physical property of the compound 3-3 is shown in Table 18.

TABLE 18 Compound 3-3 minor isomer; IR (neat film) 3345, 1752, 1683,1652, 1456, 1306, 1232, 1093, 1037, 1007 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.56 (d, J = 8.2, 2H), 7.38-7.41 (m, 3H), 6.85 (s, 1H), 6.23 (s, 1H),6.20 (br, 1H), 5.89 (s, 1H), 5.86 (s, 1H), 5.70 (dd, J = 8.4, 7.2 Hz,1H), 4.95 (s, 2H), 4.69 (dd, J = 11.0, 7.2 Hz, 1H), 4.57 (dd, J = 11.0,8.4 Hz, 1H), 4.29 (dd, J = 9.3, 3.9 Hz, 1H), 3.88 (q, J = 7.1 Hz, 1H),3.80 (s, 3H), 3.46 (dd, J = 13.7, 3.9 Hz, 1H), 3.21 (dd, J = 13.7, 9.3Hz, 1H), 2.21 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 1.45 (d, J = 7.1 Hz,3H); ¹³C NMR (100 MHz, CDCI₃) δ 170.7, 168.7, 166.5, 151.8, 15.0, 151.0,147.0, 139.0, 136.7, 134.5, 133.2, 128.6, 128.4, 128.2, 128.1, 111.8,109.1, 106.3, 100.9, 97.3, 74.6, 62.7, 60.4, 57.0, 55.0, 44.9, 21.2,20.8, 15.5, 8.7; major isomer; IR (neat film) 3374, 1751, 1683, 1651,1430, 1314, 1265, 1233, 1094, 1040, 1006 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ(d, J = 8.3 Hz, 2H), 7.36-7.43 (m, 3H), 6.86 (s, 1H), 6.40 (s, 1H), 5.93(2, 1H), 5.92 (s, 1H), 5.62 (dd, J = 8.9, 5.8 Hz, 1H), 5.50 (s, 1H),5.15 (br, 1H), 5.03 (d, J = 6.8 Hz, 1H), 5.021 (d, J = 6.8 Hz, 1H), 4.76(dd, J = 11.7, 8.9 Hz, 1H), 4.60 (dd, 11.7, 5.8 Hz, 1H), 4.34 (dd, J =10.7, 3.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 1H), 3.84 (s, 3H), 3.81 (dd, J =14.2, 3.9 Hz, 1H), 2.84 (dd, J = 14.2, 10.7 Hz, 1H), 2.25 (s, 3H), 2.13(s, 3H), 2.07 (s, 3H), 1.15 (d, J = 7.1 Hz, 1H); ¹³C MHz, CDCl₃) δ170.7, 170.3, 166.9, 152.2, 151.0, 150.8, 146.8, 138.9, 136.6, 134.1,133.4, 128.6, 128.4, 128.3, 128.2, 112.5, 108.9, 106.5, 101.0, 96.2,74.6, 62.0, 60.4, 54.9, 53.3, 52.5, 41.5, 20.8, 18.0, 15.6, 8.7;

Synthesis of Compound 3-4

To the CH₂Cl₂ (100 ml) solution of compound 3-3 (19.3 g, 26.4 mmol) andtrimethylamine (11.8 ml, 84.6 mmol), MsCl (2.60 ml, 33.8 mmol) was addedat 0° C., then stirred for 1 hour. EtOAc (400 ml) was added to thereaction solution and washed by 1N HCl, saturated NaHCO₃ aqueoussolution and brine, then dried by MgSO₄. After concentrated by vacuum,the residue was purified by silica gel chromatography (in 70% EtOAcm-hexane). Thus, the mecyl body (19.4 g, 24.0 mmol, 91%) was obtained asa yellow solid.

To the CH₃CN (15 ml) solution of mecyl body (3.00 g, 3.71 mmol) and(Boc)₂O (1.36 g, 6.22 mmol) was added and stirred for 6.5 hours. EtOAcwas added to the reaction solution and washed with 0.5N HCl, saturatedNaHCO₃ aqueous solution and brine. The organic layer was dried by MgSO₄,concentrated by vacuum and the residue was purified by silica gelchromatography (in 50% EtOAc n-hexane). Thus the compound 3-4 (3.27 g,3.60 mmol, 97%) was obtained as a yellow solid. The physical property ofthe compound 3-4 is shown in Table 19.

TABLE 19 Compound 3-4 major isomer; IR (neat film) 1775, 1733, 1670,1455, 1429, 1368, 1308, 1285, 1244, 1172, 1148, 1066, 970, 937 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.58 (d, J = 6.8 Hz, 2H), 7.33-7.41 (m, 3H), 6.87(s, 1H), 6.82 (s, 1H), 5.97 (s, 1H), 5.96 (s, 1H), 5.56, (dd, J = 8.0,8.0 Hz, 1H), 5.14 (dd, J = 8.0, 4.8 Hz, 1H), 4.95 (d, J = 10.0 Hz, 1H),4.91 (d, J = 10.0 Hz, 1H), 4.63 (dd, J = 10.8, 8.0 Hz, 1H), 4.56 (dd, J= 10.8, 8.0 Hz, 1H), 3.98 (q, J = 8.0, 1H), 3.78 (s, 3H), 3.53 (dd, J =14.8, 4.8 Hz, 1H), 3.23 (dd, J = 14.8, 8.0 Hz, 1H), 3.16 (s, 3H), 2.20(s, 3H), 2.19 (s, 3H), 2.03 (s, 3H), 1.45 (d, J = 8.0 Hz, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 170.5, 167.8, 166.0, 151.8, 150.9, 149.5, 147.3,144.1, 142.5, 136.8, 134.9, 132.9, 128.7, 128.4, 128.4, 128.2, 115.3,115.1, 113.1, 102.1, 97.5, 84.4, 74.6, 62.0, 60.4, 59.5, 56.5, 56.5,53.5, 44.6, 38.0, 27.8, 20.8, 20.8, 15.5, 9.9

Synthesis of Compound 3-5

To the EtOH (100 ml) and CH₂Cl₂ (10 ml) mixed solution of the compound3-4 (4.11 g, 4.52 mmol), H₂SO₄ (3.0 ml, 9.0 mmol in 3.0M EtOH solution)and NaBH₄ (867 mg, 22.9 mmol) were added at 0° C. After acetone (10 ml)was added, neutralized by saturated NaHCO₃ aqueous solution, added EtOAcand filtrated by Cellite. Then concentrated by vacuum, EtOH was added tothe residue and washed by saturated NaHCO₃ aqueous solution. The organiclayer was dried by MgSO₄, concentrated by vacuum and aminal (4.19 g) wasobtained. The obtained aminal is dissolved in toluene (40 ml), CSA (1.07g, 4.61 mmol) and quinoline (0.82 ml, 7.0 mmol) are added and heatrefluxed for 3 hours. EtOAc is added to the reaction solution and washedby 1N HCl aqueous solution, saturated NaHCO₃ aqueous solution and brineaqueous solution. The organic layer is dried by MgSO₄, concentrated byvacuum and the residue was purified by silica gel chromatography (in 50%EtOAc n-hexane). Thus the compound 3-5 (3.54 g, 3.97 mmol 88%) wasobtained as a yellow solid. The physical property of the compound 3-5 isshown in Table 20.

TABLE 20 Compound 3-5 [α]D²⁷ +2.9° (c = 2.97, CHCl₃); IR (neat film)1742, 1692, 1463, 1418, 1362, 1336, 1240, 1172, 1065, 1005, 962, 890,805 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 6.8 Hz, 2H), 7.36-7.44(m, 3H), 6.87 (br, 1H), 6.69 (s, 1H), 6.21 (s, 1H), 6.01 (s, 1H), 5.96(s, 1H), 4.97 (s, 2H), 4.93 (br, 1H), 4.85 (br, 2H), 3.80 (s, 3H), 3.19(s, 3H), 2.91 (br, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.04 (s, 3H), 1.32(s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 170.3, 151.5, 151.3, 151.1, 150.9,150.1, 150.1, 150.1, 146.7, 143.1, 143.0, 142.2, 142.1, 136.7, 136.6,135.8, 134.7, 134.7, 132.0, 131.5, 129.2, 129.1, 128.4, 128.2, 127.9,127.9, 127.9, 127.7, 126.2, 121.3, 120.8, 115.4, 115.2, 114.0, 113.9,101.7, 97.0, 96.5, 80.8, 80.7, 77.3, 77.2, 77.0, 76.7, 74.2, 62.4, 62.3,60.1, 60.0, 57.2, 55.7, 39.1, 38.8, 37.4, 37.4, 27.8, 27.5, 20.4, 16.3,15.2, 9.6;

Synthesis of Compound 3-6

Pd₂(dba)₃ (325 mg, 0.36 mmol, 5 mol %) was added to CH₃CN (50 ml)solution of the compound 3-5 (6.27 g, 7.02 mmol), P(o-tol)₃ (428 mg,1.41 mmol, equivalent) and triethylamine (4.0 ml, 29 mmol, 4.1equivalent) and refluxed by heating for 2 hours. After EtOAc was addedto the reaction solution and concentrated, EtOAc is added to the residueand washed by 10% citric acid, saturated NaHCO₃ aqueous solution andbrine. The organic layer was dried by MgSO₄, concentrated by vacuum andthe residue was purified by silica gel chromatography (in 50% EtOAcn-hexane). Thus the compound 3-6 (4.44 g, 5.81 mmol, 83%) was obtainedas a yellow solid. The physical property of the compound 3-6 is shown inTable 21.

TABLE 21 Compound 3-6 [α]D²⁷ +38.4° (c = 1.85, CHCl₃); IR (neat film)1743, 1699, 1636, 1424, 1367, 1309, 1233, 1173, 1113, 1065, 861, 808cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.70 (m, 5H), 6.60-6.75 (br, 1H),6.30-6.50 (br, 1H), 5.65-6.20 (br, 3H), 4.20-5.30 (br, 8H), 3.80 (s,3H), 3.09 (s, 3H), 2.90-3.30 (br, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 1.68(s, 3H), 1.46 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 149.7, 148.8,147.0, 142.9, 142.6, 137.6, 132.3, 128.5, 127.8, 125.7, 115.2, 115.2,114.0, 113.2, 113.1, 113.0, 113.0, 112.9, 101.8, 96.3, 95.4, 81.1, 74.1,73.3, 60.3, 60.2, 59.9, 54.0, 54.0, 52.6, 50.5, 37.5, 31.9, 28.3, 20.1,15.7, 9.9

Example 4

Processes and all products in each process in synthesis of the compound4-8 contained in general formula 2 are shown in following synthesisprocess D.

Synthetic Process D;

Detail of Synthesis of D; Synthesis of Compound 4-1

2N NaOH aqueous solution (0.5 ml, 1 mmol) was added to MeOH solution(1.5 ml) of the compound 3-6 (120 mg, 0.157 mmol) was added and refluxedby heating for 2.5 hours. Et₂O and water were added to the reactionsolution and acidificated by 1N HCl aqueous solution, then extracted byEtOAc. The organic layer was washed by saturated NaHCO₃ aqueous solutionand brine and concentrated by vacuum. To the residue, pyridine (0.26 ml,3.2 mmol) acetic acid anhydride (0.15 ml, 1.6 mmol) and DMPA (1 mg,0.008 mmol) were added at room temperature. After concentrated byvacuum, the residue was purified by silica gel chromatography (in 30%EtOAc n-hexane). Thus the compound 4-1 (106 mg, 0.145 mmol, 93%) wasobtained as a white solid. The physical property of the compound 4-1 isshown in Table 22.

TABLE 22 Compound 4-1 [α]D²⁶ +46.6° (c = 1.27, CHCl₃); IR (neat film)1766, 1746, 1699, 1634, 1484, 1427, 1368, 1307, 1208, 1183, 1109, 1081,937, 913, 862; ¹H NMR (40 MHz, CDCl₃) δ 7.26,-7.42 (m, 5H), 6.64 (br,1H), 6.13 (br, 1H), 5.70-5.95 (br, 3H), 4.15-5.30 (br, 8H), 3.73 (s,3H), 2.90-3.20 (br, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 1.89 (s, 3H), 1.51(s, 3H), 1.39 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 169.2, 169.1,149.8, 149.7, 149.7, 148.8, 146.8, 146.7, 144.3, 141.8, 140.4, 137.6,137.6, 132.1, 132.1, 128.6, 128.5, 128.0, 128.0, 128.0, 127.9, 127.8,127.7, 127.7, 127.7, 127.6, 127.5, 127.5, 127.5, 127.5, 125.7, 125.7,125.7, 125.7, 115.3, 115.2, 115.2, 115.2, 115.2, 112.6, 112.2, 112.2,112.2, 112.2, 101.6, 101.5, 81.0, 81.0, 81.0, 74.1, 74.1, 74.1, 73.6,60.2, 59.6, 54.0, 52.8, 52.7, 52.7, 52.5, 52.5, 50.8, 50.8, 50.7, 50.7,50.7, 32.0, 28.3, 20.6, 20.6, 20.0, 15.7, 9.3;

Synthesis of Compound 4-2

To the CH₂Cl₂ (12 ml) solution of the compound 4-1 (2.56 g, 3.51 mmol),TFA (3.0 ml, 39 mmol) was added at room temperature and stirred for 4hours. The reaction solution was poured into saturated NaHCO₃ aqueoussolution and extracted by CH₂Cl₂. After organic layer was concentratedby vacuum, the residue is dissolved in CH₂Cl₂ (12 ml) and saturatedNaHCO₃ aqueous solution (20 ml) was added. To the reaction solution,TrocCl (0.47 ml, 3.5 mmol) was added and stirred for 10 minutes. Theorganic layer is dried by MgSO₄ and concentrated by vacuum. The residuewas purified by silica gel chromatography (in 40% EtOAc n-hexane). Thusthe compound 4-2 (2.08 g, 2.59 mmol, 1.74%) is obtained as a whitepowder. The physical property of the compound 4-2 is shown in Table 23.

TABLE 23 Compound 4-2 [α]D²⁶ +39.5 39.5 (c = 1.07, CHCl₃); IR (neatfilm) 1763, 1724, 1684, 1636, 1486, 1429, 1368, 1353, 1298, 1222, 1209,1184, 1124, 1078, 1031 ,913, 863; ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.50 (m5H), 6.74 (s, 1H), 6.22 & 6.20 (s, 1H), 6.00 & 5.96 (s, 1H), 5.87 & 5.77(s, 2H), 6.72 & 4.50-5.25 (m, 9H), 4.37 & 4.29 (s, 1H), 3.79 (s, 3H),3.10-3.30 (m 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.95 (s, 3H), 1.55 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.3, 169.2, 149.8, 144.3, 141.8,137.4, 132.5, 128.5, 128.5, 127.9, 127.8, 127.6, 125.7, 124.8, 115.0,112.5, 112.2, 101.5, 95.1, 75.0, 74.0, 73.8, 60.2, 53.9, 53.3, 52.5,32.2, 31.8, 20.6, 19.9, 15.7, 9.2;

Synthesis of Compound 4-3

To the MeOH (15.0 ml) solution of the compound 4-2 (681 mg, 0.847 mmol)dimethyloxilan (0.1M acetone solution, 15 ml, 1.5 mmol) was added at 0°C. and stirred for 2 hours. To the reaction solution, Na₂SO₄ (10 g) wasadded and stirred for 10 minutes, then CSA (7.2 mg, 0.03 mmol) was addedand the temperature is elevated to room temperature. To the reactionsolution, pyridine (25 μl, 0.31 mmol) was added so as to neutralize,then filtrated and concentrated by vacuum. The residue was purified bysilica gel chromatography (in 50% EtOAc n-hexane) and the methoxycompound was obtained as a yellow powder.

THF solution (0.80 ml) of methoxy compound was added into TFA solution(4.0 ml) of NaBH₃CN (160 mg, 2.54 mmol) at 0° C. and stirred for 40minutes. CHCl₃ was added to the reaction solution and neutralized bysaturated NaHCO₃ aqueous solution. The residue was passed through acolumn of basic alumina by EtOAc, then concentrated by vacuum. Theresidue was purified by silica gel chromatography (in 50% EtOAcn-hexane). Thus the compound 4-3 (150 mg, 0.182 mmol, 7.4%) was obtainedas a white powder. The physical property of the compound 4-3 is shown inTable 24.

TABLE 24 Compound 4-3 [α]D²² +33.2 (c = 1.23, CHCl₃); IR (neat film)3510, 1764, 1722, 1664, 1484, 1428, 1369, 1342, 1304, 1227, 1185, 1126,1062, 938, 911 cm⁻¹; IR NMR (400 MHz, CDCI3) δ 7.54 (d, J = 6.8 Hz, 2H),7.38-7.48 (m, 3H), 6.83 & 6.80 (s, 1H), 6.36 & 6.33 (s, 1H), 5.78-5.87(m, 3H), 5.40 (br, 1H), 5.26-5.30 (m, 1H), 5.11-5.16 (m 1H), 4.70-4.93(m, 3H), 4.52 (br, 1H), 4.44 (m, 1H), 3.91 & 3.87 (s, 3H), 3.55-3.65(br, 2H), 3.00-3.30 (m, 3H), 2.29 & 2.28 (s, 3H), 2.22 (s, 3H), 1.95 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 170.3, 170.2, 169.8, 169.1,152.0, 151.6, 149.4, 149.0, 148.5, 146.5, 146.4, 144.3, 144.2, 142.0,142.0, 135.2, 135.2, 133.4, 133.2, 129.4, 129.2, 129.2, 129.1, 129.0,129.0, 128.9, 127.3, 127.2, 122.3, 121.8, 113.7, 113.5, 113.1, 113.0,101.7, 101.6, 95.2, 95.1, 77.2, 76.4, 75.2, 75.1, 62.7, 62.6, 6.5, 6.5,59.5, 53.9, 53.2, 47.5, 46.9, 31.9, 31.6, 2.7, 2.6, 2.6, 15.7, 9.3;

Synthesis of Compound 4-4

To the DMF solution (0.10 ml) of the compound 4-3 (101 mg, 0.123 mmol)and imidazole (21.3 mg, 0.313 mmol), TBSCl (28.0 mg, 0.186 mmol) wasadded at room temperature and stirred for 2 hours. The reaction solutionwas purified by silica gel chromatography an 40% EtOAc n-hexane) andsilanylether (106 mg, 0.127 mmol, 92%) was obtained as an oil.

Silanylether (524 mg, 0.560 mmol) was dissolved in G/GHNO₃ solution (8.0ml) and stirred for 2.5 hours at 40° C. EtOAc is added to the reactionsolution and washed by 1N HCl aqueous solution, saturated NaHCO₃ aqueoussolution and brine. The organic layer was dried by Na₂SO₄ andconcentrated by vacuum. The residue is purified by silica gelchromatography (in 50% EtOAc n-hexane). Thus the compound 4-4 (405 mg,0.475 mmol, 85%) is obtained as a yellow powder. The physical propertyof the compound 4-4 is shown in Table 25.

TABLE 25 Compound 4-4 [α]D²³ −33.7° (c = 1.48, CHCl₃); IR (neat film)3309, 1723, 1640, 1423, 1345, 1304, 1257, 1133, 1127, 1095, 838 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.54 (m 5H), 6.87 & 6.83 (s, 1H), 6.30 (br,1H), 5.35-5.73 (m 5H), 5.17-5.28 (m, 1H), 5.06-5.16 (m, 1H), 4.98 & 4.90(d, J = 12.0 Hz, 1H), 4.60-4.86 (m, 3H), 4.27-4.40 (m, 3H), 4.08 (br,1H), 3.80 & 3.74 (s, 3H), 3.15-3.35 (m, 3H), 2.28 (s, 3H), 1.94 & 1.91(s, 3H), 0.69 & 0.68 (s, 9H), −0.27 & −0.30 (s, 3H), −0.32 & −0.35 (s,3H); ¹³C NMR (100 MHz, CDCI₃) δ 151.9, 151.3, 150.1, 149.4, 148.7,146.0, 136.6, 136.4, 133.2, 132.8, 129.2, 129.1, 128.7, 128.7, 128.6,128.5, 128.4, 128.4, 126.5, 126.3, 123.2, 116.1, 106.3, 106.2, 105.0,100.2, 95.0, 75.5, 75.3, 75.1, 68.3, 67.3, 63.1, 62.9, 62.0, 60.2, 58.7,58.7, 53.6, 53.0, 48.8, 47.9, 32.2, 25.5, 17.8, 17.8, 15.6, 15.6, 8.4,8.4, −5.9, −6.0, −6.1, −6.2

Synthesis of Compound 4-5

To the CH₃CN (6.0 ml) solution of the compound 4-4 (404 mg, 0.474 mmol)and K₂CO₃ (196 mg, 1.42 mmol) BnBr (73.0 μl, 0.615 mmol) was added andrefluxed by heat for 1 hour. CHCl₃ was added to the reaction solutionand filtrated by Celite, then concentrated by vacuum. The residue waspurified by silica gel chromatography (in 50% EtOAc n-hexane). Thus thecompound 4-5 (409 mg, 0.434 mmol, 91%) was obtained as a yellow powder.The physical property of the compound 4-5 is shown in Table 26.

TABLE 26 Compound 4-5 [α]D²³ −37.4° (c = 2.11, CHCl₃); IR (neat film)3749, 1717, 1419, 1340, 1253, 1111, 838 cm−1; 1H NMR (400 MHz, CDCl₃) δ7.30-7.60 (m, 10H), 6.77 & 6.73 (s, 1H), 5.83 (s, 1H), 5.77 (br, 2H),5.69 (s, 1H), 5.51 (br, 1H), 5.22 & 5.21 (d, J = 10.0 Hz, 1H), 5.14 (br,1H), 5.00 & 4.88 (d, J = 11.6 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 4.68(d, J = 10.0 Hz, 1H), 4.59 (d, J = 10.8 Hz, 1H), 4.50 & 4.46 (d, J =11.6 Hz, 1H), 4.37 & 4.25, (br, 1H), 4.30 & 4.29 (d, J = 10.8 Hz, 1H),4.05 & 3.95 (br, 2H), 3.80 & 3.75 (s, 3H), 3.13-3.37 (m, 3H), 1.99 &1.96 (s, 9H), −0.27 & −0.32 (s, 3H), −0.33 & −0.36 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 170.2, 152.1, 152.1, 150.0, 148.8, 146.2, 137.2, 137.1,136.5, 133.1, 129.2, 128.7, 128.6, 128.6, 128.5, 128.5, 128.0, 127.9,127.8, 126.4, 126.3, 123.3, 115.8, 108.1, 102.6, 100.6, 75.5, 75.3,75.2, 70.8, 67.5, 66.7, 63.5, 62.3, 60.3, 60.3, 59.8, 53.4, 52.7, 47.9,47.2, 32.0, 31.5, 25.5, 22.6, 17.8, 15.5, 14.1, 8.7, −6.0, −6.3

Synthesis of Compound 4-6

To the THF solution (2.0 ml) of the compound 4-5 (224 mg, 0.238 mmol),Red-Al (1.3M toluene solution, 0.25 ml, 0.325 mmol) was added at 0° C.1N HCl aqueous solution was added to the reaction solution and extractedby ETOAc. The organic layer was washed by saturated NaHCO₃ aqueoussolution and brine, dried by MgSO₄ and concentrated by vacuum. Theresidue was purified by silica gel chromatography (in 30% EtOAcn-hexane). Thus the compound 4-6 (181 mg, 0.195 mmol, 82%) was obtainedas a white solid. The physical property of the compound 4-6 is shown inTable 26.

TABLE 27 Compound 4-6 [α]D²² −37.4° (c = 1.19, CHCl₃); IR (neat film)1717, 1435, 1263, 1118, 1024, 840 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.58(d, J = 8.0 Hz, 1H), 7.50 (d, J = 6.8 Hz, 1H), 7.26-7.49 (m, 8H), 6.77 &6.73 (s, 1H), 6.41 & 6.40 (s, 1H) 5.86 (s, 1H), 5.77 (s, 1H), 5.57 &5.51 (s, 1H), 5.41 (br, 1H), 5.21 (dd, J = 10.4, 10.4 Hz, 1H), 4.93 (dd,J = 7.2, 6.0 Hz, 1H), 4.69-5.02 (m, 5H), 4.20-4.35 (m, 3H), 3.87 & 3.83(s, 3H), 3.74 (m, 1H), 3.14-3.35 (m, 3H), 2.73 (dd, J = 17.6, 6.0 Hz,1zh9, 2.21 (s, 3H), 2.09 (s, 3H), 0.71 & 0.69 (s, 9H), −0.21 & −0.26 (s,3H), −0.27 & 0.31 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.1, 153.5,151.8, 149.5, 149.4, 148.1, 147.6, 146.5, 138.2, 137.4, 137.3, 131.4,131.2, 130.2, 129.9, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7,127.2, 127.2, 125.5, 125.0, 124.4, 120.7, 120.6, 107.9, 101.9, 101.7,100.7, 100.6, 95.4, 92.1, 92.1, 75.5, 75.2, 75.0, 74.8, 70.3, 68.9,68.3, 68.1, 66.7, 60.5, 60.3, 60.2, 60.1, 60.0, 59.9, 48.5, 48.1, 47.5,46.7, 30.7, 30.5, 25.6, 17.8, 15.7, 15.7, 8.7, −5.9, −5.9, −6.0, −6.0

Synthesis of Compound 4-7

To the CH₂Cl₂ (5.0 ml) solution of the compound 4-6 (2.95 g, 0.318 mmol)and TMSCN (127 μl, 0.952 mmol, 3.0 equivalent), BF₃.OEt₂ (in 1.0M CH₂Cl₂solution, 480 μl, 0.48 mmol) was added at 0° C. The reaction solutionwas poured into saturated NaHCO₃ aqueous solution, extracted by CH₂Cl₂,and organic layer was dried by MgSO₄ then concentrated by vacuum. Theresidue was purified by silica gel chromatography (in 50% EtOAcn-hexane) and nitrile compound (221 mg, 0.232 mmol) was obtained as awhite solid. To the reaction solution of nitrile compound (221 mg, 0.232mmol), acetic anhydride (11.0 ml) and pyridine (2.0 ml), DMPA (5.6 mg,0.05 mmol) was added and stirred for 1 hour at room temperature. Afterreaction solution is concentrated by vacuum, residue is purified bysilica gel chromatography (in 30% EtOAc n-hexane) and the compound 4-7(213 mg, 0.214 mmol, 92%) was obtained as a white solid. Physicalproperties of the Compound 4-7 are shown in Table 28.

TABLE 28 Compound 4-7 [α]D²³ +49.9° (c = 1.82, CHCl₃); IR (neat film)1720, 1430, 1251, 1122, 840 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.65(m, 10H), 6.52, 6.49 (s, 1H), 6.10 (br, 1H), 5.67 (s, 1H), 5.50 & 5.35(s, 1H), 5.37 (s, 1H), 4.55-5.30 (m, 8H), 5.50-5.55 (m, 3H), 3.89 & 3.83(s, 3H), 3.65-3.80 8br, 1H), 3.40-3.55 (br, 2H), 2.85 & 2.80 (dd, J =17.6, 8.0 Hz, 1H), 2.20-2.30 (br, 6H), 1.90-2.00 (br, 3H), 1.53 & 1.65(d, J = 17.0 Hz, 1H), 0.77 (br, 9H), −0.04 & 0.11 (s, 3H), −0.08 & −0.14(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.2, 170.1, 152.6, 152.2, 151.0,150.8, 149.0, 148.9, 147.6, 147.0, 146.7, 139.7, 139.7, 137.6, 137.4,137.2, 131.2, 130.9, 130.6, 128.6, 128.6, 128.5, 128.4, 128.1, 128.0,127.8, 127.7, 127.1, 125.4, 124.9, 124.9, 124.8, 117.9, 1117.9, 117.8,115.6, 115.6, 109.4, 109.3, 103.6, 103.5, 100.5, 95.2, 95.1, 75.6, 75.1,74.8, 70.4, 70.2, 63.3, 63.1, 61.9, 61.2, 60.2, 59.3, 54.2, 54.0, 51.8,51.6, 50.2, 49.3, 49.1, 48.7, 29.8, 29.7, 25.7, 20.8, 20.8, 18.1, 18.1,15.5, 8.9, −5.7, −5.8, −6.0, −6.1;

Synthesis of Compound 4-8

To the CH₃CN (2.0 ml) solution of the compound 4-7 (200 mg, 0.20 mmol),HF (48 wt % aqueous solution, 1.0 ml, 28 mmol) was added and stirred for3 hours. The reaction solution is poured into saturated NaHCO₃ aqueoussolution and extracted by EtOAc. The organic layer was washed by brineand concentrated by vacuum. The residue was purified by silica gelchromatography (in 40% AcOEt n-hexane) and alcohol compound (180 mg,0.20 mmol, 100%) was obtained as a white solid. To the CH₂Cl₂ (2.5 ml)solution of Dess-Martin reagent (103 mg, 0.243 mmol) was added at roomtemperature and stirred for 30 minutes Reaction was stopped by adding2-propanol (20 μL), then Et₂O was added, filtrated by Celite andconcentrated by vacuum. The residue was dissolved in EtOAc and washed bysaturated NaHCO₃ aqueous solution and brine. The organic layer was driedby MgSO₄ and concentrated by vacuum. The residue was purified by silicagel chromatography (in 40% EtOAc n-hexane) and the compound 4-8 (165 mg,0.188 mmol, 92%) was obtained as a white solid.

Dess-Martin reagent is shown by following chemical formula.

Physical properties of the Compound 4-7 are shown in Table 29.

TABLE 29 Compound 4-8 [α]D²⁴ +23.2° (c = 0.90, CHCl₃); IR (neat film)1732, 1607, 1584, 1488, 1382, 1315, 1238, 1122, 1035, 939, 906, 826cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.17 & 9.12 (d, 2.8H), 7.23-7.45 (m,10H), 6.61 & 6.59 (s, 1H), 5.93 (br, 1H), 5.80 (br, 1H), 5.75 & 5.72(br, 1H), 5.62 (br, 1H), 5.21 & 5.18 (d, J = 10.8 Hz, 1H), 4.65-5.00 (m,8H), 4.27-4.52 (M, 3H), 3.78 & 3.71 (s, 3H), 3.68 (br, 1H), 3.13 & 3.08(dd, J = 17.6, 8.0 Hz, 1H), 2.12 (br, 1H), 2.04-2.11 (br, 6H), 2.01 &2.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.9, 196.4, 170.2, 152.4,152.1, 146.7, 139.8, 137.1, 137.1, 132.0, 130.5, 128.6, 128.5, 128.4,128.0, 127.9, 127.9, 127.8, 127.2, 127.2, 127.0, 125.0, 124.9, 123.9,113.5, 113.4, 110.4, 103.9, 100.9, 95.0, 75.3, 74.4, 70.5, 70.4, 68.9,68.4, 62.3, 60.5, 56.8, 51.8, 51.7, 50.1, 49.1, 47.2, 30.0, 20.9, 15.8,9.0

Synthesis of Compound 4-8

THF (1.2 ml) solution of the compound 4-8 (51.2 mg, 0.058 mmol) and 10%Pd—C (51.1 mg, 0.024 mmol) was stirred for 18 hours at room temperatureunder the 1 atmospheric pressure of hydrogen gas. The reaction solutionwas filtrated by Cellite and concentrated by vacuum. The residue waspurified by silica gel chromatography (in 50% EtOAc n-hexane) and thecompound 4-9 (34.2 mg, 0.049 mmol, 84%) was obtained as a yellow film.Physical properties of the Compound 4-7 are shown in Table 30.

TABLE 30 Compound 4-9 [α]D²⁴ +23.1° (c = 1.37, CHCl₃); IR (neat film)3749, 1722, 1623, 1587, 1501, 1435, 1380, 1317, 1265, 1232, 1127, 1105,1056, 1032, 1012, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.55 (s, 1H), 5.92(s, 1H), 5.85 & 5.80 (s, 1H), 5.83 8s, 1H), 4.91 & 4.87 (d, J = 8.0 Hz,1H), 4.87 & 4.85 8d, J = 11.6 Hz, 1H), 4.69 & 4.67 (d, J = 11.6 Hz, 1H),4.48 (d, 10.4 Hz, 1H), 4.46 (m, 1H), 4.19 (br, 1H), 4.07 (br, 1H), 3.77& 3.76 (s, 3H), 3.66 (dd, J = 10.8, 8.0 Hz, 1H), 3.34 & 3.31 (dd, J =10.4, 2.8 Hz, 1H), 3.25 (dd, J = 17.6, 8.0 Hz, 1H), 2.85 & 2.80 (d, J =17.6 Hz, 1H), 2.25 & 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.3,153.1, 152.5, 149.3, 149.2, 145.9, 145.9, 144.0, 143.7, 142.5, 142.3,135.4, 135.3, 131.6, 131.3, 130.1, 130.1, 123.1, 122.9, 117.0, 116.9,115.9, 115.8, 110.0, 109.9, 108.0, 101.0, 95.3, 95.0, 75.3, 75.1, 68.9,68.8, 64.1, 61.6, 61.5, 61.1, 61.0, 58.9, 58.8, 56.3, 49.6, 48.9, 47.1,46.4, 30.5, 29.6, 20.2, 15.7, 15.7, 8.6

Example 5

Synthesis of compounds contained in general formula 1. Each process fromreaction 5-1 to reaction 5-3 and products from each process are shown insynthetic process E.

Synthetic Process E;

Details of Synthetic Process E; Synthesis of Compound 5-1

To the CH₂Cl₂ (1.2 ml) solution of the compound 4-9 (34.2 mg, 0.049mmol) and i-Pr₂NEt (0.20 ml, 1.2 mmol), AllylBr (40 μl, 0.47 mmol) wasadded and heat refluxed for 3 hours. CH₂Cl₂ was added to the reactionsolution, washed by 1N HCl aqueous solution, saturated NaHCO₃ aqueoussolution and brine. The organic layer was dried by MgSO₄ andconcentrated by vacuum. The residue was purified by silica gelchromatography (in 50% EtOAc n-hexane) and allylether (32.3 mg, 0.044mmol, 89%) was obtained.

To the MeOH (0.6 ml) solution of the allylether (32.3 mg, 0.044 mmol),K₂CO₃ (70.8 mg, 0.51 mmol) was added and stirred for 30 minutes at roomtemperature. EtOAc was added to the reaction solution, and washed by 10%citric acid, saturated NaHCO₃ aqueous solution and brine. The organiclayer was washed by MgSO₄ and concentrated by vacuum. The residue waspurified by silica gel chromatography (in 50% EtOAc n-hexane) and thecompound 5-1 (30.3 mg, 0.044 mmol, 99%) was obtained as a colorlessfilm. Physical properties of the Compound 5-1 are shown in Table 31.

TABLE 31 Compound 5-1 [α]D²⁶ +43.8° (c = 1.11, CHCl₃); IR (neat film)3298, 1720, 1486, 1434, 1378, 1336, 1315, 1267, 1229, 1125, 1058, 1032,965, 827 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.59 & 9.57 (s, 1H), 6.81 &6.78 (s, 1H), 6.20 (m, 1H), 5.65-5.95 (m, 4H), 5.40-5.60 (m, 2H),4.60-5.00 (m, 4H), 4.50 (m, 2H), 4.20-4.40 (m, 2H), 4.00 (m, 1H), 3.84 &3.82 (s, 3H), 3.60 (m, 1H), 3.20-3.35 (m, 3H), 2.86 (d, J = 17.6 Hz,1H), 2.24 & 2.23 (s, 3H), 2.06 & 2.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)δ 152.8, 152.2, 149.4, 149.3, 148.7, 147.4, 147.0, 145.8, 135.4, 135.3,133.0, 132.7, 132.0, 130.5, 130.1, 126.5, 126.5, 123.8, 123.0, 121.7,121.3, 115.7, 115.7, 110.2, 109.5, 109.4, 107.9, 100.9, 100.9, 95.1,15.0, 77.2, 76.1, 75.6, 75.5, 75.2, 68.9, 68.7, 68.5, 65.5, 65.5, 62.0,61.4, 60.6, 60.6, 59.3, 59.3, 58.3, 58.2, 49.8, 48.6, 47.4, 47.0, 30.7,30.7, 30.6, 15.8;

Synthesis of Compound 5-2

To the CH₂Cl₂ (1.60 ml) solution of the compound 5-1 (51.0 mg, 0.073mmol) and S-acetyl-N-alloccystein (42.7 mg, 0.173 mmol), WSCD.HCl (37.2mg, 0.194 mmol) and DMAP (1.9 mg, 0.008 mmol) were added at roomtemperature. After stirred for 10 minutes, CH₂Cl₂ was added to thereaction solution, and washed by 1N HCl aqueous solution, saturatedNaHCO₃ aqueous solution and brine. The organic layer was concentrated byvacuum, and the residue was purified by silica gel chromatography (in50% EtOAc n-hexane) and ester (64.0 mg, 0.070 mmol, 94%) was obtained asa yellow film.

To the CH₃CN (0.80 ml) solution of ester (29.5 mg, 0.032 mmol),hydrazine solution (upper layer of 1:3 mixture (by volume) of hydrazinehydride and CH₃CN₃, 35 μl) was added and stirred for 1.5 minutes at roomtemperature. CHCl₃ was added to the reaction solution, washed by 1N HClaqueous solution, saturated NaHCO₃ aqueous solution and brine and driedby Na₂SO₄. Solution was evaporated off and the compound 5-2 (27.8 mg,0.03 μmol, 98%) was obtained as a colorless film. Physical properties ofthe Compound 5-2 are shown in Table 32.

TABLE 32 Compound 5-2 [α]D²⁴ +22.8° (c = 1.11, CHCl₃); IR (neat film)3297, 1718, 1507, 1436, 1375, 1338, 1298, 1263, 1125, 1102, 1059, 1032,1013, 968, 939, 827 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.50-9.65 (m, 1H),7.26-7.40 (m, 5H), 6.72-6.83 (m, 1H), 6.23 (m, 1H), 6.12 & 6.09 (d, J =4.0 Hz, 1H), 5.95 (s, 1H), 5.88 (m, 1H), 5.81, (s, 1H), 5.79 & 5.69 (s,1H) 5.20-5.60 (m, 4H), 4.77-5.02 (m, 3H), 4.63-4.72 (m, 1H), 4.27-4.64(m, 4H), 4.08-4.27 (m, 3H), 3.95-4.68 (m, 1H), 3.87 (s, 3H), 3.89 (s,3H), 3.15-3.35 (m, 2H), 2.70-3.05 (m, 1H), 2.88 8d, J = 17.6 Hz, 1H),2.50-2.70 (m, 2H), 2.27 & 2.25 (s, 3H), 2.08 (s, 3H), 0.85-1.45 (m, 2H);¹³C NMR (100 MHz, CDCl₃) δ 169.8, 169.5, 155.3, 152.8, 152.2, 149.6,149.5, 148.6, 148.5, 147.5, 147.0, 145.9, 135.3, 132.7, 132.5, 132.4,132.3, 132.0, 132.0, 131.0, 130.6, 126.7, 126.6, 123.9, 123.2, 121.7,121.6, 121.1, 118.4, 118.2, 118.1, 115.6, 115.6, 110.0, 109.0, 109.2,108.4, 108.2, 101.0, 95.2, 95.1, 76.2, 75.6, 75.6, 75.3, 68.9, 68.7,68.6, 66.2, 66.1, 66.0, 65.1, 61.9, 61.4, 60.8, 60.7, 59.1, 58.8, 56.7,55.2, 55.1, 54.8, 52.8, 49.7, 48.8, 47.1, 46.9, 46.8, 31.6, 30.5, 30.3,30.1, 27.2, 26.8, 26.5, 22.6, 15.9, 15.8, 15.8, 14.2, 14.1, 8.6;

Synthesis of Compound 5-3

To the trifluoroethanol solution of the compound 5-2 (24.6 mg, 0.028mmol), TFA (10% 2,2,2-trifluoroetanol, 0.15 ml, 0.19 mmol) was added atroom temperature and stirred for 3 hours. Benzene was added to thereaction solution and concentrated by vacuum. The obtained residue wasdissolved in acetate anhydride (0.1 ml) and pyridine (0.2 ml), then DMAP(1.5 mg, 0.012 mmol) was added and stirred for 30 minutes. The reactionsolution was concentrated by vacuum and the residue was purified in PTLC(30% EtOAc n-hexane). The compound 5-3 (18.0 mg, 0.020 mmol, 71%) wasobtained as a colorless film. Physical properties of the Compound 5-3are shown in Table 33.

TABLE 33 Compound 5-3 [α]D²³ −22.2° (c = 1.06, CHCl₃); IR (neat film)3402, 1759, 1721, 1510, 1431, 1372, 1332, 1309, 1265, 1236, 1193, 1125,1101, 1-87, 1060, 1029, 1007, 983, 916, 826 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 6.79 & 6.78 (s, 1H), 6.18 (m, 1H), 6.10 (s, 1H), 6.01 & 5.99(s, 1H), 5.94 (m, 1H), 5.45-5.68 (m, 2H), 5.22-5.35 (m, 3H), 4.97-5.15(m, 3H), 4.65-4.90 (m, 3H), 4.42-4.63 (m, 5H), 4.33 (br, 1H), 4.15-4.27(m, 4H), 3.81 & 3.87 (s, 3H), 3.43 (s, 1H), 3.12-3.29 (m, 2H), 2.30-2.38(m, 2H), 2.29 & 2.28 (s, 3H), 2.26 & 2.25 (s, 3H), 2.03 (s, 3H); 13C NMR(100 MHz, CDCl₃) δ 170.4, 168.6, 168.5, 155.3, 152.6, 152.2, 149.5,148.8, 148.7, 146.0, 146.0, 141.0, 140.3, 140.3, 134.6, 134.5, 132.9,132.7, 132.7, 132.6, 130.1, 129.6, 127.1, 126.5, 125.1, 125.0, 119.5,119.4, 118.1, 116.2, 116.2, 116.2, 116.0, 115.9, 113.9, 112.7, 112.6,102.1, 102.1, 95.2, 95.0, 75.3, 75.3, 73.4, 72.7, 65.9, 61.3, 61.3,60.4, 60.4, 59.4, 59.4, 58.4, 58.2, 58.0, 57.7, 53.8, 49.0, 48.1, 47.9,47.7, 41.2, 41.1, 32.9, 32.9, 28.1, 27.7, 20.5, 20.4, 15.8, 15.8, 9.6;

Reference Example 1

Processes and products at each process regarding the synthesis ofecteinascidin 743 from the compound 5-3 is shown in following syntheticprocess F.

Synthetic Process F;

Detail of Synthesis of F; Synthesis of Compound 6-1

To the Et₂O (0.40 ml) solution of the compound 5-3 (17.3 mg, 0.0190mmol) and zinc powder (96.1 mg, 1.47 mmol), AcOH (0.20 ml) was added atroom temperature and stirred for 2.5 hours. Reaction solution wasfiltrate by Celite and concentrated by vacuum. EtOH was added to theresidue and washed by saturated NaHCO₃ and brine. The organic layer wasconcentrated by vacuum and the residue was purified refined by PTLC (in50% EtOAc n-hexane), thus amine (12.8 mg, 0.0175 mmol, 92%) was obtainedas a colorless film. To amine (5.6 mg, 0.0076 mmol), aqueous solution(30 μl) of formalin and MeOH (0.4 ml) solution of NaBH₃CN (12 mg, 0.19mmol), AcOH (0.10 ml) was added and stirred at room temperature for 1hour. After concentrated by vacuum, the reaction solution was diluted byEtOAc and washed by saturated NaHCO₃ and brine. The organic layer wasconcentrated by vacuum, and the residue was purified by PTLC (in 50%EtOAct n-hexane), then the compound 6-1 (5.5 mg, 0.0074 mmol, 96%) wasobtained as a colorless film. Physical properties of the Compound 6-1are shown in Table 34.

TABLE 34 Compound 6-1 [α]D²³ −25.6° (c = 0.86, CHCl₃); IR (neat film)3401, 1759, 1724, 1507, 1446, 1372, 1331, 1235, 1194, 1145, 1106, 1088,1067, 998, 915 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.78 (s, 1H), 6.08 (s,1H), 6.08 (m, 1H), 5.99 (s, 1H9, 5.96 (m, 1H), 5.45 (d, J = 17.6 Hz,1H), 5.31 (d, J = 17.6 Hz, 1H), 5.25 (d, J = 10.8 Hz, 2H), 5.02 (d, J =12.0 Hz, 1H), 4.80 (m, 2H), 4.40-4.55 (m, 3H), 4.27-4.40 (m, 2H), 4.24(s, 1H), 4.19 (m, 1H), 4.16 (m, 2H), 3.79 (s, 3H), 3.35-3.45 (m 2H),2.85-2.97 (m, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.20-2.40 (m, 1H), 2.20(s, 3H), 2.13 (d, J = 16.4 Hz, 1H), 2.03 (s, 3H); ¹³C NMR (100 MHz,CDCl₃) δ 170.4, 168.6, 155.4, 150.8, 148.8, 145.7, 140.9, 140.3, 134.5,132.8, 131.7, 129.9, 124.7, 124.6, 120.2, 118.0, 116.6, 113.5, 113.3,102.0, 72.9, 65.8, 61.3, 60.4, 59.2, 59.1, 55.0, 54.5, 53.8, 41.6, 41.5,32.8, 23.7, 20.4, 15.7, 9.6

Synthesis of Compound 6-2

To the CH₂Cl₂ (0.70 ml) solution of the compound 6-1 (8.6 mg, 0.012mmol), Pd(PPh₃)Cl₂ (3.2 mg, 0.0045 mmol) and AcOH (15 μl, 0.26 mmol, 23equivalent), n-Bu₃SnH (30 μl, 0.11 mmol) was added at room temperaturefor 20 minutes. The reaction solution was diluted by Et₂O, and afterfiltrated by Celite, concentrated by vacuum. The residue was refined bysilica gel chromatography (in 10% MeOH CH₂Cl₂) and amine (6.4 mg, 0.010mmol, 89%) was obtained as a white film.

To the mixed solvent of DMF (0.15 ml) and CH₂Cl₂ (0.15 ml) of amine (3.7mg, 0.0059 mmol), 4-formyl-N-methylpyridine (16.5 mg, 0.057 mmol, 10equivalent) was added and stirred at room temperature for 15 min. DBU(8.0 μl, 0.053 mmol) was added to the reaction solution and stirred atroom temperature for 15 min. The reaction solution was diluted by CH₂Cl₂(0.30 ml), then saturated citric acid aqueous solution (100 μl) wasadded and stirred for 40 minutes. Saturated NaHCO₃ aqueous solution andEt₂O were added, then Et₂O layer was concentrated by vacuum. The residuewas purified by PTLC (in 70% EtOAc n-hexane), and the compound 6-2 (2.0mg, 0.0032 mmol, 54%) was obtained as a white film. Physical propertiesof the Compound 6-2 are shown in Table 35.

TABLE 35 Compound 6-2 [α]D²² +153° (c = 0.20, CHCl₃); IR (neat film)3447, 1763, 1723, 1622, 1589, 1500, 456, 373, 1270, 1236, 1194, 1160,1145, 1108, 1087, 1063 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.49 (s, 1H),6.11 (s, 1H), 6.03 (s, 1H), 5.69 (s, 1H), 5.09 (d, J = 11.6 Hz, 1H),4.66 (br, 1H), 4.39 (s, 1H), 4.24 (d, J = 4.8 Hz, 1H), 4.22 (d, J = 11.6Hz,, 1H), 4.16 (d, J = 2.8 Hz, 1H), 3.76 (s, 3H), 3.54 (d, J = 4.8 Hz,1H), 3.43 (dd, J = 9.6, 2.8 Hz, 1H), 2.90 (dd, J = 18.4, 9.6 Hz, 1H),2.84 (d, J = 13.6 Hz, 1H), 2.70 (d, J = 18.4 Hz, 1H), 2.57 (d, J = 13.6Hz, 1H), 2.33 (s, 3H9, 2.24 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 186.7, 168.5, 160.5, 147.1, 146.4, 142.9, 141.6,140.7, 130.4, 129.8121.7, 121.7, 120.0, 117.9, 117.1, 113.5, 113.3,102.2, 61.7, 61.4, 60.3, 59.8, 58.9, 54.6, 43.2, 41.6, 36.8, 24.1, 20.4,15.8, 9.7

Synthesis of Compound 6-3

To the EtOH (0.25 ml) solution of the compound 6-2 (2.0 mg, 0.0026 mmol)and 3-hydroxy-4-methoxyphenylethylamine (12.4 mg, 0.062 mmol), NaOAc(7.4 mg, 0090 mmol) was added at room temperature and stirred for 5.5hours. After concentrated by vacuum, the residue was purified by PTLC(5% MeOH in CH₂Cl₂) and the compound 6-3 (2.4 mg, 0.0031 mmol, 96%) wasobtained as a white film. Physical properties of the Compound 6-3 areshown in Table 36.

TABLE 36 Compound 6-3 [α]D²³ −57.0° (c = 0.24, CHCl₃); IR (neat film)3437, 2931, 1743, 1591, 1507, 1456, 1369, 1236, 1193, 1107, 1087, 1053,1028 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.60 (s, 1H), 6.48 (s, 1H), 6.45(s, 1H), 6.05 (s, 1H), 5.98 (s, 1H), 5.73 (s, 1H), 5.38 (br, 1H), 5.02(d, J = 11.6 Hz, 1H), 4.57 (br, 1H), 4.33 (s, 1H), 4.28 (d, J = 5.2 Hz,1H), 4.19 (d, J = 2.8 Hz, 1H), 4.12 (dd, J = 11.6, 2.8 Hz, 1H), 3.79 (s,3H), 3.63 (s, 3H), 3.51 (d, J = 4.8 Hz, 1H), 3.42 (m, 1H), 3.10 (ddd, J= 11.6, 10.8, 4.0 Hz, 1H), 2.94 (m, 2H), 2.78 (m, 1H), 2.62 (m, q1H),2.47 (m, 1H), 2.35 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H),2.09 (m, 1H), 2.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 168.1,147.8, 145.3, 144.5, 144.3, 143.0, 141.3, 140.1, 130.8, 129.3, 129.1,125.8, 121.2, 120.7, 118.2, 118.1, 114.1, 114.1, 113.4, 109.8, 101.9,64.6, 61.1, 60.4, 60.0, 59.7, 59.5, 55.2, 54.7, 54.6, 42.2, 41.8, 41.6,39.6, 28.8, 24.2, 20.5, 15.8, 9.7;

Synthesis of Compound 6-4

To the CH₂CN (0.3 ml) and H₂O (0.2 ml) mixed solution of the compound6-3 (2.4 mg, 0.031 mmol, 1.0 equivalent), AgNO₃ (10.2 mg, 0.060 mmol)was added and stirred at room temperature for 17 hours. EtOAc was addedto the reaction solution, washed by saturated NaHCO₃ aqueous solutionand the organic layer was dried by Na₂SO₄. Then concentrated by vacuum,and the compound 6-4 was obtained as a yellow film. Physical propertiesof the Compound 6-4 are shown in Table 37.

TABLE 37 Compound 6-4 [α]D²² −58.0° (c = 0.15, CH₂Cl₂); IR (neat film)3347, 2930, 1763, 1741, 1590, 1509, 1458, 1431, 1369, 1237, 1195, 1122,1109, 1088, 1053, 1029, 1003, 958, 916 cm⁻¹; ¹H NMR (400 MHz,) δ 6.61(s, 1H), 6.47 (s, 1H), 6.45 (s, 1H), 6.02 (s, 1H), 5.94 (s, 1H), 5.698br, 1H), 5.39 (br, 1H), 5.13 (d, J = 11.2 Hz, 1H), 4.81 (s, 1H), 4.48(d, J = 3.3 Hz, 1H), 4.48 (br, 1H), 4.16 (d, J = 5.1 Hz, 1H), 4.05 (dd,J = 11.2 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 3.57 8d, J = 4.9 Hz, 1H),3.22 (br, 1H), 3.12 (ddd, J = 10.0, 10.0, 4.0 Hz, 1H), 2.82-2.97 (m,2H), 2.81 (m, 1H), 2.60 (ddd, J = 15.9, 10.0, 4.0 Hz, 1H), 2.48 (ddd, J= 15.9, 4.0, 3.4 Hz, 1H), 2.37 (br, 1H), 2.32 (s, 3H), 2.27 (s, 3H),2.20 (s, 3H), 2.19 (br, 1H), 2.03 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ172.6, 168.3, 147.7, 145.1, 144.4, 144.2, 142.9, 141.3, 140.5, 131.5,129.2, 129.1, 121.8, 120.9, 117.9, 115.9, 114.0, 112.5, 109.8, 101.7,82.1, 64.7, 61.3, 60.4, 57.8, 57.7, 56.0, 55.1, 54.9, 42.2, 42.1, 41.4,39.7, 28.9, 24.1, 20.5, 15.8, 9.7;

Illustration List of Abbreviations

MOMO: methoxymethoxyTFA: trifluoroacetic acidTF: trifluoromethanesulfonyl

Silyl Groups

-   TIPS: tri isopropylsilyl group-   TBS: t-butyldimethyl silyl group-   TBDPS: t-butyl diphenyl silyl group-   TES: triethylsilyl group-   TMS: trimethylsilyl group-   Dppf: diphenyl phosphiferrocene-   Ts p-toluenesulfonyl-   CSA: camphor sulfonic acid-   Bn: benzyl-   TMG: N,N,N,N-tetramethylguanidine-   PMP: paramethoxyphenyl-   TABF: tetrabutylammonium florid-   DMAP: dimethylaminopyridine-   Ms: methanesulfonyl-   TEM: triethylamine-   Boc: tertiary butoxycarbonyl-   Dba: trans,trans-dibenzylidene acetone-   Troc: trichloroethoxycarbonyl-   G/GHNO₃: guanidineaqueous solution-   Red-AI: [(MeOCH₂CH₂)₂AlH2] Na-   Alloc: allyloxycarbonyl-   WSCDD.HCl: 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric    acid salt-   DBU: diazabicyclo[5,4,0]undecene-7-en

INDUSTRIAL APPLICABILITY

As mentioned above, by utilizing the intermediates and reactionprocesses of the present invention, various intermediates and analoguesof Et743 can be provided, further excellent effect that these compoundscan be effectively produced is provided.

1. An intermediate compound for total synthesis of ecteinascidinscomprising, a compound represented by general formula 1 having thioethergroup at C₄ site, and the substituent R₂ of N₁₂ site istrichloroethoxicarbonyl to which various substituents can be introducedby mild condition, further having 10 members ring structure which can beconverted to a ring of other numbered members,

wherein, Y is O or NH, X₂, X₃ and X₄ are independently selected from thegroup consisting of H or alkyl group of carbon number 4 or less,alkoxyalkyl group, allyl group, or alkyl or arylsulfonyl group, R₁ andR₄ is H or alkyl group of carbon number 4 or less, R₂ is alkoxycarbonylgroup which can be substituted by halogen, lower alkyl sulfonyl or arylsulfonyl group and R₃ is nitrile or OH.
 2. The intermediate compound ofclaim 1 as represented by general formula 1, produced by the processesdisplayed by reactions 5-1, 5-2 and 5-3,

wherein, the reaction 5-1 is transforming reaction of C₁₋₈ hydroxylgroup to allyl ether and C₂₂ acetyl group to hydroxyl group, thereaction 5-2 is introducing reaction of cysteine into C₂₂ acetyl groupand the reaction 5-3 is C₄ thioetherification reaction and transformingreaction of C₅ hydroxyl group to acetyl group, wherein Y is O, X₂ is Ac,X₃ is H, R₁ is Me, R₂ is Troc, R₃ is CN, and X₄ and R₄ are same as togeneral formula
 1. 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. An amine compound whichprovide a segment forming a chemical structural site of A ring side ofthe intermediate compound of general formula 3 represented by generalformula 4,

wherein, R₄, X₂, Y and X₁ is same as to these of general formula 2, byUgi reaction.
 10. The amine compound of claim 9, wherein Y is O, X₁ isselected from silyl groups consisting of acyl group of carbon number 4or less, TBDPS, TIPS, TBS, TES and TMS.
 11. The amine compound of claim10 represented by general formula 4, produced by the processes displayedby reactions 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7 and 2-8,

wherein the reaction 2-1 is transforming reaction from C₅ hydroxyl groupto methoxymethyl group, the reaction 2-2 is introducing reaction ofhydroxyl group to C₂₂, the reaction 2-3 is Mannich reaction, thereaction 2-4 is transforming reaction of C₆ hydroxyl group totrifluoromethanesulfonyl group, reaction 2-5 is the reducing reaction oflactone, reaction 2-6 is transforming reaction of C₂₂ hydroxyl to TBDPSgroup, reaction 2-7 is methylation reaction of C₆ TfO group and thereaction 2-8 is the transforming reaction to amine, wherein Y=0, X₁ isTBOPS, X₂ is MOM and R₄ is Me.
 12. A carboxylic acid compound whichprovides a segment forming a chemical structural site of E ring side ofthe intermediate compound of general formula 3 represented by generalformula 5 by Ugi reaction,

wherein, R₁, R₂ and R₄, X₃ and X₄ are same as to these of generalformula
 1. 13. The carboxylic acid compound of claim 12, wherein, X₃ andX₄ are independently selected from the group consisting of H or alkylgroup, alkoxyalkyl group, allyl group of carbon number 4 or less, allylgroup, alkyl or arylsulfonyl group, R₂ is alkoxycarbonyl group, loweralkylsulfonyl or arylsulfonyl group which can be substituted by halogen.14. The carboxylic compound of claim 13 represented by general formula5, produced by the processes displayed by reactions 1-1, 1-2, 1-3, 1-4,1-5 1-6 and 1-7

wherein the reaction 1-1 is introducing reaction of formyl group to C₂₀,the reaction 1-2 is transforming reaction of C₂₀ formyl group todimethylacetal, the reaction 1-3 is iodizing reaction of C₁₉ and acidicdehydrolysing reaction, the reaction 1-4 is transforming reaction ofC₁₋₈ hydroxyl group to benzyl group, the reaction 1-6 is Honor Emonsreaction, reaction 1-6 is asymmetric reducing reaction by Duphos-Rhsynthetic catalyst and the reaction 1-7 is the dehydrolysing reaction ofmethylester, wherein, R₂ is Boc, X₃ is Bn, X₄ is Me, and R₁ is same asto these of general formula 2.